Immunobinders directed against tnf

ABSTRACT

Isolated binding proteins, e.g., antibodies or antigen binding portions thereof, which bind to tumor necrosis factor-alpha (TNF-α), e.g., human TNF-α, and related antibody-based compositions and molecules are disclosed. Also disclosed are pharmaceutical compositions comprising the antibodies, as well as therapeutic and diagnostic methods for using the antibodies.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/550,587, filed Oct. 24, 2011, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

TNF-α binding proteins and their uses in the prevention and/or treatmentof acute and chronic immunological diseases are provided.

2. Background of the Invention

There is a need in the art for improved binding proteins capable ofbinding TNF-α (also referred to as tumor necrosis factor, tumor necrosisfactor-alpha, tumor necrosis factor-α, TNF, and cachectin). Provided area novel family of binding proteins, CDR grafted binding proteins,humanized binding proteins, and fragments thereof, capable of bindingTNF-α with high affinity and neutralizing TNF-α.

BRIEF SUMMARY OF THE INVENTION

TNF-α binding proteins, or antigen-binding portions thereof, that bindTNF-α are provided. In an embodiment, the antigen binding domaincomprises the VH region chosen from any one of SEQ ID NOs: 22, 24, 26,28, 30, 32, 34-58, 74-83, 94-266, 478-486, 496-675, 738-762, 778-956,1053-1062, 1073, 1075, and 1077, or one, two, or three CDRs therefrom.In another embodiment, the antigen binding domain comprises the VLregion chosen from any one of SEQ ID NOs: 23, 25, 27, 29, 31, 33, 59-73,84-93, 267-477, 487-495, 676-737, 763-777, 957-1052, 1063-1072, 1074,1076, and 1078, or one, two, or three CDRs therefrom. In a particularembodiment, the antigen binding domain comprises a VH region and a VLregion, for example, wherein the VH region comprises SEQ ID NOs: 22, 24,26, 28, 30, 32, 34-58, 74-83, 94-266, 478-486, 496-675, 738-762,778-956, 1053-1062, 1073, 1075, and 1077, or one, two, or three CDRstherefrom, and the VL region comprises SEQ ID NOs: 23, 25, 27, 29, 31,33, 59-73, 84-93, 267-477, 487-495, 676-737, 763-777, 957-1052,1063-1072, 1074, 1076, and 1078, or one, two, or three CDRs therefrom.

In an embodiment, the binding protein binds TNF-α. In anotherembodiment, the binding protein modulates a biological function ofTNF-α. In another embodiment, the binding protein neutralizes TNF-α. Inyet another embodiment, the binding protein diminishes the ability ofTNF-α to bind to its receptor, for example, the binding proteindiminishes the ability of pro-human TNF-α, mature-human TNF-α, ortruncated-human TNF-α to bind to its receptor. In yet anotherembodiment, the binding protein reduces one or more TNF-α biologicalactivities selected from: TNF-dependent cytokine production;TNF-dependent cell killing; TNF-dependent inflammation; TNF-dependentbone erosion; and TNF-dependent cartilage damage.

In an embodiment, the binding protein has an on rate constant (K_(on))selected from: at least about 10²M⁻¹ s⁻¹; at least about 10³M⁻¹ s⁻¹; atleast about 10⁴M⁻¹ s⁻¹; at least about 10⁵M⁻¹ s⁻¹; and at least about10⁶M⁻¹ s⁻¹; as measured by surface plasmon resonance. In anotherembodiment, the binding protein has an off rate constant (K_(off))selected from: at most about 10⁻³ s⁻¹; at most about 10⁻⁴ s⁻¹; at mostabout 10⁻⁵ s⁻¹; and at most about 10⁻⁶ s⁻¹, as measured by surfaceplasmon resonance. In yet another embodiment, the binding protein has adissociation constant (K_(D)) selected from: at most about 10⁻⁷ M; atmost about 10⁻⁸ M; at most about 10⁻⁹ M; at most about 10⁻¹⁰ M; m atmost about 10⁻¹¹ M; at most about 10⁻¹² M; and at most 10⁻¹³M.

In another aspect, a method for treating a mammal is provided comprisingadministering to the mammal an effective amount of the pharmaceuticalcomposition disclosed herein. In another embodiment, a method forreducing human TNF-α activity is provided, the method comprising:contacting human TNF-α with the binding protein disclosed herein suchthat human TNF-α activity is reduced. In another embodiment, provided isa method for reducing human TNF-α activity in a human subject sufferingfrom a disorder in which TNF-α activity is detrimental, the methodcomprising administering to the human subject the binding proteindisclosed herein such that human TNF-α activity in the human subject isreduced. In another embodiment, provided is a method for treating asubject for a disease or a disorder in which TNF-α activity isdetrimental, the method comprising administering to the subject thebinding protein disclosed herein such that treatment is achieved.

In one embodiment, the method treats diseases involving immune andinflammatory elements, such as autoimmune diseases, particularly thoseassociated with inflammation, including Crohn's disease, psoriasis(including plaque psoriasis), arthritis (including rheumatoid arthritis,psoriatic arthritis, osteoarthritis, or juvenile idiopathic arthritis),multiple sclerosis, and ankylosing spondylitis. Therefore, the bindingproteins herein may be used to treat these disorders.

DETAILED DESCRIPTION OF THE INVENTION

Provided are TNF-α binding proteins, or antigen-binding portionsthereof, that bind TNF-α, pharmaceutical compositions thereof, as wellas nucleic acids, recombinant expression vectors and host cells formaking such binding proteins and fragments. Also provided are methods ofusing the binding proteins disclosed herein to detect human TNF-α, toinhibit human TNF-α either in vitro or in vivo, and to regulate geneexpression or TNF-α related functions.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present disclosure shall have the meanings that arecommonly understood by those of ordinary skill in the art. The meaningand scope of the terms should be clear, however, in the event of anylatent ambiguity, definitions provided herein take precedent over anydictionary or extrinsic definition. Further, unless otherwise requiredby context, singular terms shall include pluralities and plural termsshall include the singular. In this application, the use of “or” means“and/or”, unless stated otherwise. Furthermore, the use of the term“including”, as well as other forms of the term, such as “includes” and“included”, is not limiting. Also, terms such as “element” or“component” encompass both elements and components comprising one unitand elements and components that comprise more than one subunit unlessspecifically stated otherwise.

Generally, nomenclatures used in connection with, and techniques of,cell and tissue culture, pathology, oncology, molecular biology,immunology, microbiology, genetics and protein and nucleic acidchemistry and hybridization described herein are those well known andcommonly used in the art. The methods and techniques of the presentdisclosure are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification unless otherwise indicated. See, e.g., Sambrook et al.Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. (1989)). Enzymatic reactionsand purification techniques are performed according to manufacturer'sspecifications, as commonly accomplished in the art or as describedherein. The nomenclatures used in connection with, and the laboratoryprocedures and techniques of, analytical chemistry, synthetic organicchemistry, and medicinal and pharmaceutical chemistry described hereinare those well known and commonly used in the art. Standard techniquesare used for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients.

The term “human TNF-α” (abbreviated herein as hTNF-α) includes atrimeric cytokine protein. The term includes a homotrimeric proteincomprising three 17.5 kD TNF-α proteins. The homotrimeric protein isreferred to as a “TNF-α protein”. The term human “TNF-α” is intended toinclude recombinant human TNF-α (rhTNF-α), which can be prepared bystandard recombinant expression methods. The sequence of human TNF-α isshown in Table 1.

TABLE 1 Sequence of Human TNF-α Sequence Identi- Sequence Protein fier12345678901234567890123456789012 Human SEQVRSSSRTPSDKPVAHVVANPQAEGQLQWLNDR TNF-α ID NO.: 1ANALLANGVELRDNQLVVPSEGLYLIYSQVLF KGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEK GDRLSAEINRPDYLDFAESGQVYFGIIAL

The term “antibody”, broadly refers to any immunoglobulin (Ig) molecule,or antigen binding portion thereof, comprised of four polypeptidechains, two heavy (H) chains and two light (L) chains, or any functionalfragment, mutant, variant, or derivation thereof, which retains theessential epitope binding features of an Ig molecule. Such mutant,variant, or derivative antibody formats are known in the art.

In a full-length antibody, each heavy chain is comprised of a heavychain variable region (abbreviated herein as HCVR or VH) and a heavychain constant region. The heavy chain constant region is comprised ofthree domains, CH1, CH2 and CH3. Each light chain is comprised of alight chain variable region (abbreviated herein as LCVR or VL) and alight chain constant region. The light chain constant region iscomprised of one domain, CL. The VH and VL regions can be furthersubdivided into regions of hypervariability, termed complementaritydetermining regions (CDR), interspersed with regions that are moreconserved, termed framework regions (FR). Each VH and VL is composed ofthree CDRs and four FRs, arranged from amino-terminus tocarboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3,CDR3, FR4. Immunoglobulin molecules can be of any type (e.g., IgG, IgE,IgM, IgD, IgA and IgY), class (e.g., IgG 1, IgG2, IgG 3, IgG4, IgA1 andIgA2) or subclass.

The term “antigen-binding portion” or “antigen-binding region” of abinding protein (or simply “binding protein portion”), refers to one ormore fragments of a binding protein that retain the ability tospecifically bind to an antigen (e.g., hTNF-α). The antigen-bindingfunction of a binding protein can be performed by fragments of afull-length binding protein. Such binding protein embodiments may alsohave bispecific, dual specific, or multi-specific formats; specificallybinding to two or more different antigens. Examples of binding fragmentsencompassed within the term “antigen-binding portion” of a bindingprotein include (i) a Fab fragment, a monovalent fragment consisting ofthe VL, VH, CL and CH1 domains; (ii) a F(ab′)₂ fragment, a bivalentfragment comprising two Fab fragments linked by a disulfide bridge atthe hinge region; (iii) a Fd fragment consisting of the VH and CH1domains; (iv) a Fv fragment consisting of the VL and VH domains of asingle arm of an antibody, (v) a dAb fragment (Ward et al. (1989) Nature341:544-546, Winter et al., PCT publication WO 90/05144 A1), whichcomprises a single variable domain; and (vi) an isolated complementaritydetermining region (CDR). Furthermore, although the two domains of theFv fragment, VL and VH, are coded for by separate genes, they can bejoined, using recombinant methods, by a synthetic linker that enablesthem to be made as a single protein chain in which the VL and VH regionspair to form monovalent molecules (known as single chain Fv (scFv); see,e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988)Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain bindingproteins are also intended to be encompassed within the term“antigen-binding portion” of a binding protein. Other forms of singlechain binding proteins, such as diabodies are also encompassed.Diabodies are bivalent, bispecific binding proteins in which VH and VLdomains are expressed on a single polypeptide chain, but using a linkerthat is too short to allow for pairing between the two domains on thesame chain, thereby forcing the domains to pair with complementarydomains of another chain and creating two antigen binding sites (see,e.g., Holliger, et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448;Poljak, et al. (1994) Structure 2:1121-1123).

The term “binding protein” refers to a polypeptide comprising one ormore antigen-binding portions disclosed herein optionally linked to alinker polypeptide or a constant domain. Linker polypeptides comprisetwo or more amino acid residues joined by peptide bonds and are used tolink one or more antigen binding portions. Such linker polypeptides arewell known in the art (see e.g., Holliger, et al. (1993) Proc. Natl.Acad. Sci. USA 90:6444-6448; Poljak, et al. (1994) Structure2:1121-1123). A constant domain refers to a heavy or light chainconstant domain. Human IgG heavy chain and light chain constant domainamino acid sequences are known in the art and represented in Table 2.

TABLE 2 Sequence of Human IgG Heavy Chain Constant Domain and LightChain Constant Domain Sequence Sequence Protein Identifier12345678901234567890123456789012 Ig gamma-1 SEQ ID NO.: 2ASTKGPSVFFLAPSSKSTSGGTAALGCLVKDY constant regionFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK Ig gamma-1 SEQ ID NO.: 3ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY constant regionFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS mutant LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK Ig Kappa constant SEQ IDNO.: 4 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY regionPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Ig Lambda SEQ ID NO.: 5 QPKAAPSVTLFPPSSEELQANKATLVCLISDFconstant region YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE KTVAPTECS

A binding protein, or antigen-binding portion thereof, may be part of alarger immunoadhesion molecule, formed by covalent or noncovalentassociation of the binding protein or binding protein portion with oneor more other proteins or peptides. Examples of such immunoadhesionmolecules include use of the streptavidin core region to make atetrameric scFv molecule (Kipriyanov, et al. (1995) Hum. Antibod.Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide anda C-terminal polyhistidine tag to make bivalent and biotinylated scFvmolecules (Kipriyanov, et al. (1994) Mol. Immunol. 31:1047-1058).Antibody portions, such as Fab and F(ab′)₂ fragments, can be preparedfrom whole antibodies using conventional techniques, such as papain orpepsin digestion, respectively, of whole antibodies. Moreover, bindingproteins, binding protein portions and immunoadhesion molecules can beobtained using standard recombinant DNA techniques, as described herein.

An “isolated binding protein” refers to a binding protein, orantigen-binding portion thereof, that is substantially free of otherbinding proteins having different antigenic specificities (e.g., anisolated binding protein that specifically binds hTNF-α is substantiallyfree of binding proteins that specifically bind antigens other thanhTNF-α). An isolated binding protein that specifically binds hTNF-α may,however, have cross-reactivity to other antigens, such as TNF-αmolecules from other species. Moreover, an isolated binding protein maybe substantially free of other cellular material and/or chemicals.

The term “human binding protein” includes binding proteins, orantigen-binding portion thereof, that having variable and constantregions derived from human germline immunoglobulin sequences. The humanbinding proteins disclosed herein may include amino acid residues notencoded by human germline immunoglobulin sequences (e.g., mutationsintroduced by random or site-specific mutagenesis in vitro or by somaticmutation in vivo), for example in the CDRs and in particular CDR3.However, the term “human binding protein”, is not intended to includebinding proteins in which CDR sequences derived from the germline ofanother mammalian species, such as a mouse, have been grafted onto humanframework sequences.

The terms “Kabat numbering”, “Kabat definitions” and “Kabat labeling”are used interchangeably herein. These terms, which are recognized inthe art, refer to a system of numbering amino acid residues which aremore variable (i.e., hypervariable) than other amino acid residues inthe heavy and light chain variable regions of an antibody, or an antigenbinding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci.190:382-391 and Kabat, et al. (1991) Sequences of Proteins ofImmunological Interest, Fifth Edition, U.S. Department of Health andHuman Services, NIH Publication No. 91-3242). See also, Martin, “ProteinSequence and Structure Analysis of Antibody Variable Domains,” InKontermann and Dübel, eds., Antibody Engineering (Springer-Verlag,Berlin, 2001), Chapter 31, especially pages 432-433. For the heavy chainvariable region, the hypervariable region ranges from amino acidpositions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, andamino acid positions 95 to 106 for CDR3. For the light chain variableregion, the hypervariable region ranges from amino acid positions 24 to34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acidpositions 89 to 97 for CDR3.

The term “CDR” refers to the complementarity determining region withinantibody variable sequences. There are three CDRs in each of thevariable regions of the heavy chain and the light chain, which aredesignated CDR1, CDR2 and CDR3, for each of the variable regions. Theterm “CDR set” refers to a group of three CDRs that occur in a singlevariable region capable of binding the antigen. The exact boundaries ofthese CDRs have been defined differently according to different systems.The system described by Kabat (Kabat et al., Sequences of Proteins ofImmunological Interest (National Institutes of Health, Bethesda, Md.(1987) and (1991)) not only provides an unambiguous residue numberingsystem applicable to any variable region of an antibody, but alsoprovides precise residue boundaries defining the three CDRs. These CDRsmay be referred to as Kabat CDRs. Chothia and coworkers (Chothia andLesk (1987) J. Mol. Biol. 196:901-917) and Chothia et al. (1989) Nature342:877-883) found that certain sub-portions within Kabat CDRs adoptnearly identical peptide backbone conformations, despite having greatdiversity at the level of amino acid sequence. These sub-portions weredesignated as L1, L2 and L3 or H1, H2 and H3 where the “L” and the “H”designates the light chain and the heavy chains regions, respectively.These regions may be referred to as Chothia CDRs, which have boundariesthat overlap with Kabat CDRs. Other boundaries defining CDRs overlappingwith the Kabat CDRs have been described by Padlan (1995) FASEB J.9:133-139 and MacCallum (1996) J. Mol. Biol. 262(5):732-745. Still otherCDR boundary definitions may not strictly follow one of the abovesystems, but will nonetheless overlap with the Kabat CDRs, although theymay be shortened or lengthened in light of prediction or experimentalfindings that particular residues or groups of residues or even entireCDRs do not significantly impact antigen binding. The methods usedherein may utilize CDRs defined according to any of these systems,although particular embodiments use Kabat or Chothia defined CDRs.

Human heavy chain and light chain acceptor sequences are known in theart. In one embodiment of the disclosure the human heavy chain and lightchain acceptor sequences are selected from the sequences listed fromV-base (hvbase.mrc-cpe.cam.ac.uk/) or from IMGT®, the internationalImMunoGeneTics information system®(himgt.cines.fr/textes/IMGTrepertoire/LocusGenes/). In anotherembodiment of the disclosure the human heavy chain and light chainacceptor sequences are selected from the sequences described in Table 3and Table 4, respectively.

TABLE 3 Heavy Chain Acceptor Sequences SEQ ID Protein Sequence No.region 12345678901234567890123456789012 SEQ ID VH4-59 FR1QVQLQESGPGLVKPSETLSLTCTVSGGSISS NO: 6 SEQ ID VH4-59 FR2 WIRQPPGKGLEWIGNO: 7 SEQ ID VH4-59 FR3 RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR NO: 8 SEQ IDVH3-53 FR1 EVQLVESGGGLIQPGGSLRLSCAASGFTVSS NO: 9 SEQ ID VH3-53 FR2WVRQAPGKGLEWVS NO: 10 SEQ ID VH3-53 FR3 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNO: 11 SEQ ID JH1/JH4/JH5 WGQGTLVTVSS NO: 12 FR4 SEQ ID JH2 FR4WGRGTLVTVSS NO: 13 SEQ ID JH6 FR4 WGQGTTVTVSS NO: 14

TABLE 4 Light Chain Acceptor Sequences SEQ ID Protein Sequence No.region 12345678901234567890123456789012 SEQ ID 1-39/O12DIQMTQSPSSLSASVGDRVTITC NO: 15 FR1 SEQ ID 1-39/O12 WYQQKPGKAPKLLIY NO:16 FR2 SEQ ID 1-39/O12 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC NO: 17 FR3 SEQID 3-15/L2 FR1 EIVMTQSPATLSVSPGERATLSC NO: 18 SEQ ID 3-15/L2 FR2WYQQKPGQAPRLLIY NO: 19 SEQ ID 3-15/L2 FR3GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC NO: 20 SEQ ID JK2 FR4 FGQGTKLEIKR NO:21

The term “multivalent binding protein” is used in this specification todenote a binding protein comprising two or more antigen binding sites.The multivalent binding protein may be engineered to have the three ormore antigen binding sites, and is generally not a naturally occurringantibody. The term “multispecific binding protein” refers to a bindingprotein capable of binding two or more related or unrelated targets.Dual variable domain (DVD) binding proteins or immunoglobulins (DVD-Ig)as used herein, are binding proteins that comprise two or more antigenbinding sites and are tetravalent or multivalent binding proteins. SuchDVD-binding proteins may be monospecific, i.e., capable of binding oneantigen or multispecific, i.e., capable of binding two or more antigens.DVD-binding proteins comprising two heavy chain DVD-Ig polypeptides andtwo light chain DVD-Ig polypeptides are referred to a DVD-Ig. Each halfof a DVD-Ig comprises a heavy chain DVD-Ig polypeptide, and a lightchain DVD-Ig polypeptide, and two antigen binding sites. Each bindingsite comprises a heavy chain variable domain and a light chain variabledomain with a total of 6 CDRs involved in antigen binding per antigenbinding site. DVD binding proteins and methods of making DVD bindingproteins are disclosed in U.S. Pat. No. 7,612,181.

One aspect of the disclosure pertains to a DVD binding proteincomprising binding proteins capable of binding TNF-α. In a particularembodiment, the DVD binding protein is capable of binding TNF-α and asecond target.

The term “neutralizing” refers to neutralization of a biologicalactivity of a cytokine when a binding protein specifically binds thecytokine. In a particular embodiment, binding of a neutralizing bindingprotein to hTNF-α results in inhibition of a biological activity ofhTNF-α, e.g., the neutralizing binding protein binds hTNF-α and reducesa biologically activity of hTNF-α by at least about 20%, 40%, 60%, 80%,85% or more Inhibition of a biological activity of hTNF-α by aneutralizing binding protein can be assessed by measuring one or moreindicators of hTNF-α biological activity well known in the art. Forexample neutralization of the cytoxicity of TNF-α on L929 cells.

In another embodiment, the terms “agonist” or “agonizing” refer to anincrease of a biological activity of TNF-α when a binding proteinspecifically binds TNF-α, e.g., hTNF-α. In a particular embodiment,binding of an agonizing binding protein to TNF-α results in the increaseof a biological activity of TNF-α. In a particular embodiment, theagonistic binding protein binds TNF-α and increases a biologicallyactivity of TNF-α by at least about 20%, 40%, 60%, 80%, 85%, 90%, 95,96%, 97%, 98%, 99%, and 100%. An inhibition of a biological activity ofTNF-α by an agonistic binding protein can be assessed by measuring oneor more indicators of TNF-α biological activity well known in the art.

The term “activity” includes activities such as the bindingspecificity/affinity of a binding protein for an antigen, for example, ahTNF-α binding protein that binds to a TNF-α antigen and/or theneutralizing potency (or agonizing potency) of a binding protein, forexample, a hTNF-α binding protein whose binding to hTNF-α inhibits thebiological activity of hTNF-α, e.g., neutralization of the cytoxicity ofTNF-α on L929 cells.

The term “surface plasmon resonance” refers to an optical phenomenonthat allows for the analysis of real-time biospecific interactions bydetection of alterations in protein concentrations within a biosensormatrix, for example using the BIAcore system (Pharmacia Biosensor AB,Uppsala, Sweden and Piscataway, N.J.).

The term “K_(on)” refers to the on rate constant for association of abinding protein (e.g., an antibody) to the antigen to form, e.g., theantibody/antigen complex as is known in the art. The “K_(on)” also isknown by the terms “association rate constant”, or “ka”, as usedinterchangeably herein. This value indicating the binding rate of anantibody to its target antigen or the rate of complex formation betweenan antibody and antigen also is shown by the equation below:

Antibody(“Ab”)+Antigen(“Ag”)→Ab−Ag

The term “K_(off)” refers to the off rate constant for dissociation, or“dissociation rate constant”, of a binding protein (e.g., an antibody),from the, e.g., antibody/antigen complex as is known in the art. Thisvalue indicates the dissociation rate of an antibody from its targetantigen or separation of Ab−Ag complex over time into free antibody andantigen as shown by the equation below:

Ab+Ag←Ab−Ag

The term “K_(D)” refers to the “equilibrium dissociation constant” andrefers to the value obtained in a titration measurement at equilibrium,or by dividing the dissociation rate constant (K_(off)) by theassociation rate constant (K_(on)). The association rate constant, thedissociation rate constant and the equilibrium dissociation constant areused to represent the binding affinity of an antibody to an antigen.Methods for determining association and dissociation rate constants arewell known in the art. Using fluorescence-based techniques offers highsensitivity and the ability to examine samples in physiological buffersat equilibrium. Other experimental approaches and instruments such as aBIAcore® (biomolecular interaction analysis) assay can be used (e.g.,instrument available from BIAcore International AB, a GE Healthcarecompany, Uppsala, Sweden). Additionally, a KinExA® (Kinetic ExclusionAssay) assay, available from Sapidyne Instruments (Boise, Id.) can alsobe used.

I. Binding Proteins that Bind Human TNF-α

One aspect of the present disclosure provides isolated fully-humananti-human TNF binding proteins, such as monoclonal antibodies, orantigen-binding portions thereof, that bind to TNF-α with high affinity,a slow off rate and high neutralizing capacity. A second aspect of thedisclosure provides affinity-matured fully-human anti-TNF bindingproteins, such as monoclonal antibodies, or antigen-binding portionsthereof, that bind to TNF-α with high affinity, a slow off rate and highneutralizing capacity.

A. Method of Making TNF-α Binding Proteins

The binding proteins disclosed herein may be made by any of a number oftechniques known in the art.

1. Anti-TNF-α Monoclonal Antibodies Using Transgenic Animals

In another embodiment of the disclosure, binding proteins are producedby immunizing a non-human animal comprising some, or all, of the humanimmunoglobulin locus with a TNF-α antigen. In a particular embodiment,the non-human animal is a XENOMOUSE transgenic mouse, an engineeredmouse strain that comprises large fragments of the human immunoglobulinloci and is deficient in mouse antibody production. See, e.g., Green etal. (1994) Nature Genet. 7:13-21 and U.S. Pat. Nos. 5,916,771;5,939,598; 5,985,615; 5,998,209; 6,075,181; 6,091,001; 6,114,598 and6,130,364. See also PCT Publications WO 91/10741, published Jul. 25,1991; WO 94/02602, published Feb. 3, 1994; WO 96/34096 and WO 96/33735,both published Oct. 31, 1996; WO 98/16654, published Apr. 23, 1998; WO98/24893, published Jun. 11, 1998; WO 98/50433, published Nov. 12, 1998;WO 99/45031, published Sep. 10, 1999; WO 99/53049, published Oct. 21,1999; WO 00/09560, published Feb. 24, 2000; and WO 00/37504, publishedJun. 29, 2000. The XENOMOUSE transgenic mouse produces an adult-likehuman repertoire of fully human antibodies, and generatesantigen-specific human Mabs. The XENOMOUSE transgenic mouse containsapproximately 80% of the human antibody repertoire through introductionof megabase sized, germline configuration YAC fragments of the humanheavy chain loci and x light chain loci. See, Mendez et al. (1997)Nature Genet. 15:146-156; Green and Jakobovits (1998) J. Exp. Med.188:483-495.

2. Anti-TNF-α Monoclonal Antibodies Using Recombinant Antibody Libraries

In vitro methods also can be used to make the binding protein disclosedherein, wherein an antibody library is screened to identify an antibodyhaving the desired binding specificity. Methods for such screening ofrecombinant antibody libraries are well known in the art and includemethods described in, for example, U.S. Pat. No. 5,223,409; PCTPublications WO 92/18619; WO 91/17271; WO 92/20791; WO 92/15679; WO93/01288; WO 92/01047; WO 92/09690; and WO 97/29131; Fuchs et al. (1991)Bio/Technology 9:1369-1372; Hay et al. (1992) Hum. Antibod. Hybridomas3:81-85; Huse et al. (1989) Science 246:1275-1281; McCafferty et al.(1990) Nature 348:552-554; Griffiths et al. (1993) EMBO J. 12:725-734;Hawkins et al. (1992) J. Mol. Biol. 226:889-896; Clackson et al. (1991)Nature 352:624-628; Gram et al. (1992) Proc. Natl. Acad. Sci. USA89:3576-3580; Garrard et al. (1991) Bio/Technology 9:1373-1377;Hoogenboom et al. (1991) Nucl. Acid Res. 19:4133-4137; and Barbas et al.(1991) Proc. Natl. Acad. Sci. USA 88:7978-7982; and U.S. PatentPublication No. 2003.0186374.

The recombinant antibody library may be from a subject immunized withTNF-α, or a portion of TNF-α. Alternatively, the recombinant antibodylibrary may be from a naïve subject, i.e., one who has not beenimmunized with TNF-α, such as a human antibody library from a humansubject who has not been immunized with human TNF-α. Antibodiesdisclosed herein are selected by screening the recombinant antibodylibrary with the peptide comprising human TNF-α to thereby select thoseantibodies that recognize TNF-α. Methods for conducting such screeningand selection are well known in the art, such as described in thereferences in the preceding paragraph. To select antibodies disclosedherein having particular binding affinities for hTNF-α, such as thosethat dissociate from human TNF-α with a particular k_(off) rateconstant, the art-known method of surface plasmon resonance can be usedto select antibodies having the desired k_(off) rate constant. To selectantibodies disclosed herein having a particular neutralizing activityfor hTNF-α, such as those with a particular an IC₅₀, standard methodsknown in the art for assessing the inhibition of hTNF-α activity may beused.

In one aspect, provided is an isolated binding protein, or anantigen-binding portion thereof, that binds TNF-α, e.g., human TNF-α. Ina particular embodiment, the binding protein is a neutralizing bindingprotein. In various embodiments, the binding protein is a recombinantbinding protein or a monoclonal antibody.

For example, the binding proteins disclosed herein can also be generatedusing various phage display methods known in the art. In phage displaymethods, functional antibody domains are displayed on the surface ofphage particles which carry the polynucleotide sequences encoding them.In a particular, such phage can be utilized to display antigen-bindingdomains expressed from a repertoire or combinatorial antibody library(e.g., human or murine). Phage expressing an antigen binding domain thatbinds the antigen of interest can be selected or identified withantigen, e.g., using labeled antigen or antigen bound or captured to asolid surface or bead. Phage used in these methods are typicallyfilamentous phage including fd and M13 binding domains expressed fromphage with Fab, Fv or disulfide stabilized Fv antibody domainsrecombinantly fused to either the phage gene III or gene VIII protein.Examples of phage display methods that can be used to make the bindingproteins disclosed herein can be found in the art.

As described in the above references, after phage selection, the bindingprotein coding regions from the phage can be isolated and used togenerate whole binding proteins including human binding protein or anyother desired antigen binding fragment, and expressed in any desiredhost, including mammalian cells, insect cells, plant cells, yeast, andbacteria, e.g., as described in detail below. For example, techniques torecombinantly produce Fab, Fab′ and F(ab′)₂ fragments can also beemployed using methods known in the art such as those disclosed in PCTPublication WO 92/22324; Mullinax et al. (1992) BioTechniques12(6):864-869; and Sawai et al. (1995) Am. J. Reprod. Immunol. 34:26-34;and Better et al. (1998) Science 240:1041-1043. Examples of techniqueswhich can be used to produce single-chain Fvs and antibodies includethose described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al.(1991) Methods Enzymol. 203:46-88; Shu et al. (1993) Proc. Natl. Acad.Sci. USA 90:7995-7999; and Skerra et al. (1998) Science 240:1038-1041.

Alternative to screening of recombinant antibody libraries by phagedisplay, other methodologies known in the art for screening largecombinatorial libraries can be applied to the identification of dualspecificity binding protein disclosed herein. One type of alternativeexpression system is one in which the recombinant antibody library isexpressed as RNA-protein fusions, as described in PCT Publication No. WO98/31700 and in Roberts and Szostak (1997) Proc. Natl. Acad. Sci. USA94:12297-12302. In this system, a covalent fusion is created between anmRNA and the peptide or protein that it encodes by in vitro translationof synthetic mRNAs that carry puromycin, a peptidyl acceptor antibiotic,at their 3′ end. Thus, a specific mRNA can be enriched from a complexmixture of mRNAs (e.g., a combinatorial library) based on the propertiesof the encoded peptide or protein, e.g., antibody, or portion thereof,such as binding of the antibody, or portion thereof, to the dualspecificity antigen. Nucleic acid sequences encoding antibodies, orportions thereof, recovered from screening of such libraries can beexpressed by recombinant means as described above (e.g., in mammalianhost cells) and, moreover, can be subjected to further affinitymaturation by either additional rounds of screening of mRNA-peptidefusions in which mutations have been introduced into the originallyselected sequence(s), or by other methods for affinity maturation invitro of recombinant antibodies, as described above.

In another approach the binding proteins disclosed herein can also begenerated using yeast display methods known in the art. In yeast displaymethods, genetic methods are used to tether antibody domains to theyeast cell wall and display them on the surface of yeast. In particular,such yeast can be utilized to display antigen-binding domains expressedfrom a repertoire or combinatorial antibody library (e.g., human ormurine). Examples of yeast display methods that can be used to make thebinding proteins disclosed herein include those disclosed Wittrup et al.U.S. Pat. No. 6,699,658 and Frenken et al., U.S. Pat. No. 6,114,147.

B. Production of Recombinant TNF-α Binding Proteins

Binding proteins disclosed herein may be produced by any of a number oftechniques known in the art. For example, expression from host cells,wherein expression vector(s) encoding the heavy and light chains is(are) transfected into a host cell by standard techniques. The variousforms of the term “transfection” are intended to encompass a widevariety of techniques commonly used for the introduction of exogenousDNA into a prokaryotic or eukaryotic host cell, e.g., electroporation,calcium-phosphate precipitation, DEAE-dextran transfection and the like.Although it is possible to express the binding proteins disclosed hereinin either prokaryotic or eukaryotic host cells, expression of bindingprotein in eukaryotic cells is contemplated, for example, in mammalianhost cells, because such eukaryotic cells (and in particular mammaliancells) are more likely than prokaryotic cells to assemble and secrete aproperly folded and immunologically active binding protein.

Mammalian host cells for expressing the recombinant binding proteinsdisclosed herein include Chinese Hamster Ovary (CHO cells) (includingdhfr-CHO cells, described in Urlaub and Chasin (1980) Proc. Natl. Acad.Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., asdescribed in Kaufman and Sharp (1982) J. Mol. Biol. 159:601-621), NS0myeloma cells, COS cells and SP2 cells. When recombinant expressionvectors encoding binding protein genes are introduced into mammalianhost cells, the binding proteins are produced by culturing the hostcells for a period of time sufficient to allow for expression of thebinding protein in the host cells or, in particular, secretion of theantibody into the culture medium in which the host cells are grown.Antibodies can be recovered from the culture medium using standardprotein purification methods.

Host cells can also be used to produce functional binding proteinfragments, such as Fab fragments or scFv molecules. It will beunderstood that variations on the above procedure are within the scopeof the present disclosure. For example, it may be desirable to transfecta host cell with DNA encoding functional fragments of either the lightchain and/or the heavy chain of a binding protein disclosed herein.Recombinant DNA technology may also be used to remove some, or all, ofthe DNA encoding either or both of the light and heavy chains that isnot necessary for binding to the antigens of interest. The moleculesexpressed from such truncated DNA molecules are also encompassed by thebinding proteins disclosed herein. In addition, bifunctional bindingproteins may be produced in which one heavy and one light chain are abinding protein disclosed herein and the other heavy and light chain arespecific for an antigen other than the antigens of interest bycrosslinking a binding protein disclosed herein to a second bindingprotein by standard chemical crosslinking methods.

In an exemplary system for recombinant expression of a binding protein,or antigen-binding portion thereof, disclosed herein, a recombinantexpression vector encoding both the heavy chain and the light chain isintroduced into dhfr⁻ CHO cells by calcium phosphate-mediatedtransfection. Within the recombinant expression vector, the heavy andlight chain genes are each operatively linked to CMV enhancer/AdMLPpromoter regulatory elements to drive high levels of transcription ofthe genes. The recombinant expression vector also carries a DHFR gene,which allows for selection of CHO cells that have been transfected withthe vector using methotrexate selection/amplification. The selectedtransformant host cells are cultured to allow for expression of theheavy and light chains and intact binding protein is recovered from theculture medium. Standard molecular biology techniques are used toprepare the recombinant expression vector, transfect the host cells,select for transformants, culture the host cells and recover the bindingprotein from the culture medium. Still further a method of synthesizinga recombinant binding protein disclosed herein is provided by culturinga host cell disclosed herein in a suitable culture medium until arecombinant binding protein disclosed herein is synthesized. The methodcan further comprise isolating the recombinant binding protein from theculture medium.

II. hTNF-α Binding Proteins

A. Individual Clone Sequences

Table 5 provides the VH and VL sequences of fully human anti-human TNFbinding proteins, including CDRs from each VH and VL sequence.

TABLE 5 Individual Fully Human Anti-TNF-α VH Sequences Sequence Proteinregion 123456789012345678901234567890 AE11-1 VH SEQ ID NO.: 22EVQLVQSGAEVKKPGASVKVSCKASGYTFT SYDVNWVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTITADESTSTAYMELSSLRSED TAVYYCAIFDSDYMDVWGKGTLVTVSS AE11-1 VHCDR- Residues 31-35 SYDVN H1 of SEQ ID NO.: 22 AE11-1 VH CDR- Residues50-66 WMNPNSGNTGYAQKFQG H2 of SEQ ID NO.: 22 AE11-1 VH CDR- Residues99-106 FDSDYMDV H3 of SEQ ID NO.: 22 AE11-1 VL SEQ ID NO.: 23SYELTQPPSVSLSPGQTARITCSGDALPKQ YAYWYQQKPGQAPVLVIYKDTERPSGIPERFSGSSSGTTVTLTISGAQAEDEADYYCQSA DSSGTSWVFGGGTKLTVL AE11-1 VL CDR-Residues 23-33 SGDALPKQYAY L1 of SEQ ID NO.: 23 AE11-1 VL CDR- Residues49-55 KDTERPS L2 of SEQ ID NO.: 23 AE11-1 VL CDR- Residues 89-98SADSSGTSWV L3 of SEQ ID NO.: 23 AE11-5 VH SEQ ID NO.: 24EVQLVQSGAEVKKPGSSAKVSCKASGGTFS SYAISWVRQAPGQGLEWMGGIIPILGTANYAQKFLGRVTITADESTSTVYMELSSLRSED TAVYYCARGLYYDPTRADYWGQGTLVTVSS AE11-5 VHCDR- Residues 31-35 SYAIS H1 of SEQ ID NO.: 24 AE11-5 VH CDR- Residues50-66 GIIPILGTANYAQKFLG H2 of SEQ ID NO.: 24 AE11-5 VH CDR- Residues99-109 GLYYDPTRADY H3 of SEQ ID NO.: 24 AE11-5 VL SEQ ID NO.: 25DIVMTQSPDFHSVTPKEKVTITCRASQSIG SSLHWYQQKPDQSPKLLIRHASQSISGVPSRFSGSGSGTDFTLTIHSLEAEDAATYYCHQ SSSSPPPTFGQGTQVEIK AE11-5 VL CDR-Residues 24-34 RASQSIGSSLH L1 of SEQ ID NO.: 25 AE11-5 VL CDR- Residues50-56 HASQSIS L2 of SEQ ID NO.: 25 AE11-5 VL CDR- Residues 89-98HQSSSSPPPT L3 of SEQ ID NO.: 25 TNF-JK1 VH SEQ ID NO.: 26EVQLVESGGGLVQPGGSLRLSCATSGFTFN NYWMSWVRQAPGKGLEWVANINHDESEKYYVDSAKGRFTISRDNAEKSLFLQMNSLRAED TAVYYCARIIRGRVGFDYYNYAMDVWGQGT LVTVSSTNF-JK1 VH CDR- Residues 31-35 NYWMS H1 of SEQ ID NO.: 26 TNF-JK1 VHCDR- Residues 50-66 NINHDESEKYYVDSAKG H2 of SEQ ID NO.: 26 TNF-JK1 VHCDR- Residues 99-115 IIRGRVGFDYYNYAMDV H3 of SEQ ID NO.: 26 TNF-JK1 VLSEQ ID NO.: 27 DIRLTQSPSPLSASVGDRVTITCRASQSIGNYLNWYQHKPGKAPKLLIYAASSLQSGVPS RFSGTGSGTDFTLTISSLQPEDFATYYCQESYSLIFAGGTKVEIK TNF-JK1 VL CDR- Residues 24-34 RASQSIGNYLN L1 of SEQ IDNO.: 27 TNF-JK1 VL CDR- Residues 50-56 AASSLQS L2 of SEQ ID NO.: 27TNF-JK1 VL CDR- Residues 89-95 QESYSLI L3 of SEQ ID NO.: 27 TNF-Y7C VHSEQ ID NO.: 28 EVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYDINWVRQPTGQGLEWMGWMDPNNGNTGY AQKFVGRVTMTRDTSKTTAYLELSGLKSEDTAVYYCARSSGSGGTWYKEYFQSWGQGTMV TVSS TNF-Y7C VH CDR- Residues 31-35 NYDINH1 of SEQ ID NO.: 28 TNF-Y7C VH CDR- Residues 50-66 WMDPNNGNTGYAQKFVG H2of SEQ ID NO.: 28 TNF-Y7C VH CDR- Residues 99-112 KSSGSGGTWYKEYFQS H3 ofSEQ ID NO.: 28 TNF-Y7C VL SEQ ID NO.: 29 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQFPQLLIYLGSYRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFPPGTFGQGTKLGIK TNF-Y7C VL CDR- Residues 24-39 RSSQSLLHSNGYNYLDL1 of SEQ ID NO.: 29 TNF-Y7C VL CDR- Residues 55-61 LGSYRAS L2 of SEQ IDNO.: 29 TNF-Y7C VL CDR- Residues 94-103 MQRIEFPPGT L3 of SEQ ID NO.: 29AE11-7 VH SEQ ID NO.: 30 EVQLVQSGAEVKKPGASVKVSCKTSGYSLTQYPIHWVRQAPGQRPEWMGWISPGNGNTKL SPKFQGRVTLSRDASAGTVFMDLSGLTSDDTAVYFCTSVDLGDHWGQGTLVTVSS AE11-7 VH CDR- Residues 31-35 QYPIH H1 of SEQID NO.: 30 AE11-7 VH CDR- Residues 50-66 WISPGNGNTKLSPKFQG H2 of SEQ IDNO.: 30 AE11-7 VH CDR- Residues 99-104 VDLGDH H3 of SEQ ID NO.: 30AE11-7 VL SEQ ID NO.: 31 DIVMTQSPEFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLINYASQSFSGVPS RFSGGGSGTDFTLTINSLEAEDAATYYCHQSSNLPITFGQGTRLEIK AE11-7 VL CDR- Residues 24-34 RASQSIGSSLH L1 of SEQ IDNO.: 31 AE11-7 VL CDR- Residues 50-56 YASQSFS L2 of SEQ ID NO.: 31AE11-7 VL CDR- Residues 89-97 HQSSNLPIT L3 of SEQ ID NO.: 31 AE11-13 VHSEQ ID NO.: 32 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYPMHWVRQAPGEGLEWVSGISSNSASIGY ADSVKGRFTISRDNAQNTLYLQMNSLGDEDTAVYYCVSLTLGIGQGTLVTVSS AE11-13 VH CDR- Residues 31-35 DYPMH H1 of SEQID NO.: 32 AE11-13 VH CDR- Residues 50-66 GISSNSASIGYADSVKG H2 of SEQ IDNO.: 332 AE11-13 VH CDR- Residues 99-102 LTLG H3 of SEQ ID NO.: 32AE11-13 VL SEQ ID NO.: 33 DIRLTQSPSSLSASVGDRVTITCRASQSIGNYLHWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTLYSFGQGTKLEIK AE11-13 VL CDR- Residues 24-34 RASQSIGNYLH L1 of SEQID NO.: 33 AE11-13 VL CDR- Residues 50-56 AASSLQS L2 of SEQ ID NO.: 33AE11-13 VL CDR- Residues 89-97 QQSYSTLYS L3 of SEQ ID NO.: 33

B. IgG Converted Clones

Table 6 provides the VH sequence of humanized anti-TNF MAK-195antibodies that were converted into IgG clones as discussed in detail inExample 2.

TABLE 6 Humanized anti-TNF MAK-195 Ab VH sequences of IgG convertedclones Protein Sequence region 123456789012345678901234567890 A8 SEQ IDNO.: 34 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVNWVRQAPGKGLEWVSMIAADGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWHHGPVAYWGQGTLVTVSS A8 CDR-H1Residues 31-35 NYGVN VH of SEQ ID NO.: 34 A8 CDR-H2 Residues 50-65MIAADGFTDYASSVKG VH of SEQ ID NO.: 34 A8 CDR-H3 Residues 98-106EWHHGPVAY VH of SEQ ID NO.: 34 B5 SEQ ID NO.: 35EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVSWVRQAPGKGLEWVSLIRGDGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWHHGPVAYWGQGTLVTVSS B5 CDR-H1Residues 31-35 NYGVS VH of SEQ ID NO.: 35 B5 CDR-H2 Residues 50-65LIRGDGSTDYASSLKG VH of SEQ ID NO.: 35 B5 CDR-H3 Residues 98-106EWHHGPVAY VH of SEQ ID NO.: 35 rHC44 SEQ ID NO.: 36EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVSWVRQAPGKGLEWVSMIWADGSTHYADTLKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS rHC44 CDR-H1Residues 31-35 NYGVS VH of SEQ ID NO.: 36 rHC44 CDR-H2 Residues 50-65MIWADGSTHYADTLKS VH of SEQ ID NO.: 36 rHC44 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 36 rHC22 SEQ ID NO.: 37EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTDYADTVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS rHC22 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 37 rHC22 CDR-H2 Residues 50-65MIWADGSTDYADTVKG VH of SEQ ID NO.: 37 rHC22 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 37 rHC81 SEQ ID NO.: 38EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYADSVKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPLAYWGQGTLVTVSS rHC81 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 38 rHC81 CDR-H2 Residues 50-65MIWADGSTHYADSVKS VH of SEQ ID NO.: 38 rHC81 CDR-H3 Residues 98-106EWQHGPLAY VH of SEQ ID NO.: 38 rHC18 SEQ ID NO.: 39EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWSDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS rHC18 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 39 rHC18 CDR-H2 Residues 50-65MIWSDGSTDYASSVKG VH of SEQ ID NO.: 39 rHC18 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 39 rHC14 SEQ ID NO.: 40EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPAAYWGQGTLVTVSS rHC14 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 40 rHC14 CDR-H2 Residues 50-65MIWADGSTHYASSLKG VH of SEQ ID NO.: 40 rHC14 CDR-H3 Residues 98-106EWQHGPAAY VH of SEQ ID NO.: 40 rHC3 SEQ ID NO.: 41EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVSWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS rHC3 CDR-H1Residues 31-35 NYGVS VH of SEQ ID NO.: 41 rHC3 CDR-H2 Residues 50-65MIWADGSTHYASSLKG VH of SEQ ID NO.: 41 rHC3 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 41 rHC19 SEQ ID NO.: 42EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPAAYWGQGTLVTVSS rHC19 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 42 rHC19 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 42 rHC19 CDR-H3 Residues 98-106EWQHGPAAY VH of SEQ ID NO.: 42 rHC34 SEQ ID NO.: 43EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPSAYWGQGTLVTVSS rHC34 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 43 rHC34 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 43 rHC34 CDR-H3 Residues 98-106EWQHGPSAY VH of SEQ ID NO.: 43 rHC83 SEQ ID NO.: 44EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS rHC83 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 44 rHC83 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 44 rHC83 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 44 S4-19 SEQ ID NO.: 45EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVEWVRQAPGKGLEWVSGIWADGSTHYADTVKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-19 CDR-H1Residues 31-35 NYGVE VH of SEQ ID NO.: 45 S4-19 CDR-H2 Residues 50-65GIWADGSTHYADTVKS VH of SEQ ID NO.: 45 S4-19 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 45 S4-50 SEQ ID NO.: 46EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVEWVRQAPGKGLEWVSGIWADGSTHYADTVKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVGYWGQGTLVTVSS S4-50 CDR-H1Residues 31-35 NYGVE VH of SEQ ID NO.: 46 S4-50 CDR-H2 Residues 50-65GIWADGSTHYADTVKS VH of SEQ ID NO.: 46 S4-50 CDR-H3 Residues 98-106EWQHGPVGY VH of SEQ ID NO.: 46 S4-63 SEQ ID NO.: 47EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVEWVRQAPGKGLEWVSGIWADGSTHYADTVKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVGYWGQGTLVTVSS S4-63 CDR-H1Residues 31-35 NYGVE VH of SEQ ID NO.: 47 S4-63 CDR-H2 Residues 50-65GIWADGSTHYADTVKS VH of SEQ ID NO.: 47 S4-63 CDR-H3 Residues 98-106EWQHGPVGY VH of SEQ ID NO.: 47 S4-55 SEQ ID NO.: 48EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVGYWGQGTLVTVSS S4-55 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 48 S4-55 CDR-H2 Residues 50-65MIWADGSTDYASTVKG VH of SEQ ID NO.: 48 S4-55 CDR-H3 Residues 98-106EWQHGPVGY VH of SEQ ID NO.: 48 S4-6 SEQ ID NO.: 49EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-6 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 49 S4-6 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 49 S4-6 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 49 S4-18 SEQ ID NO.: 50EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYADSVKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPLAYWGQGTLVTVSS S4-18 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 50 S4-18 CDR-H2 Residues 50-65MIWADGSTHYADSVKS VH of SEQ ID NO.: 50 S4-18 CDR-H3 Residues 98-106EWQHGPLAY VH of SEQ ID NO.: 50 S4-31 SEQ ID NO.: 51EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVQWVRQAPGKGLEWVSGIGADGSTAYASSLKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHSGLAYWGQGTLVTVSS S4-31 CDR-H1Residues 31-35 NYGVQ VH of SEQ ID NO.: 51 S4-31 CDR-H2 Residues 50-65GIGADGSTAYASSLKG VH of SEQ ID NO.: 51 S4-31 CDR-H3 Residues 98-106EWQHSGLAY VH of SEQ ID NO.: 51 S4-34 SEQ ID NO.: 52EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVSWVRQAPGKGLEWVSMIWADGSTHYADTVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPLAYWGQGTLVTVSS S4-34 CDR-H1Residues 31-35 NYGVS VH of SEQ ID NO.: 52 S4-34 CDR-H2 Residues 50-65MIWADGSTHYADTVKG VH of SEQ ID NO.: 52 S4-34 CDR-H3 Residues 98-106EWQHGPLAY VH of SEQ ID NO.: 52 S4-74 SEQ ID NO.: 53EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYADTVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPLAYWGQGTLVTVSS S4-74 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 53 S4-74 CDR-H2 Residues 50-65MIWADGSTHYADTVKG VH of SEQ ID NO.: 53 S4-74 CDR-H3 Residues 98-106EWQHGPLAY VH of SEQ ID NO.: 53 S4-12 SEQ ID NO.: 54EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-12 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 54 S4-12 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 54 S4-12 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 54 S4-54 SEQ ID NO.: 55EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-54 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 55 S4-54 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 55 S4-54 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 55 S4-17 SEQ ID NO.: 56EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-17 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 56 S4-17 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 56 S4-17 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 56 S4-40 SEQ ID NO.: 57EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-40 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 57 S4-40 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 57 S4-40 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 57 S4-24 SEQ ID NO.: 58EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS S4-24 CDR-H1Residues 31-35 NYGVT VH of SEQ ID NO.: 58 S4-24 CDR-H2 Residues 50-65MIWADGSTHYASSVKG VH of SEQ ID NO.: 58 S4-24 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 58

Table 7 provides VL sequences of IgG converted clones for Humanizedanti-TNF MAK-195 antibodies as discussed in detail in Example 2.

TABLE 7 Humanized anti-TNF MAK-195 Ab VL sequences of IgG convertedclones Sequence Protein region 123456789012345678901234567890 hMAK195SEQ ID NO.: 59 DIQMTQSPSSLSASVGDRVTITCKASQAVS VL.1SAVAWYQQKPGKAPKLLIYWASTRHTGVPS VL RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSTPFTFGQGTKLEIKR hMAK195 CDR-L1 Residues 24-34 KASQAVSSAVA VL.1 of SEQID VL NO.: 59 hMAK195 CDR-L2 Residues 50-56 WASTRHT VL.1 of SEQ ID VLNO.: 59 hMAK195 CDR-L3 Residues 89-97 QQHYSTPFT VL.1 of SEQ ID VL NO.:59 S4-24 SEQ ID NO.: 60 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASTLHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFTFGQGTKLEIKR S4-24 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 60 S4-24 CDR-L2 Residues 50-56 WASTLHT VL of SEQ ID NO.: 60 S4-24CDR-L3 Residues 89-97 QQHYRTPFT VL of SEQ ID NO.: 60 S4-40 SEQ ID NO.:61 DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFSFGQGTKLEIKR S4-40 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 61 S4-40 CDR-L2 Residues 50-56WASTRHS VL of SEQ ID NO.: 61 S4-40 CDR-L3 Residues 89-97 QQHYRTPFS VL ofSEQ ID NO.: 61 S4-17 SEQ ID NO.: 62 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASTRHSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFTFGQGTKLEIKR S4-17 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 62 S4-17 CDR-L2 Residues 50-56 WASTRHS VL of SEQ ID NO.: 62 S4-17CDR-L3 Residues 89-97 QQHYRTPFT VL of SEQ ID NO.: 62 S4-54 SEQ ID NO.:63 DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYKTPFSFGQGTKLEIKR S4-54 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 63 S4-54 CDR-L2 Residues 50-56WASARHT VL of SEQ ID NO.: 63 S4-54 CDR-L3 Residues 89-97 QQHYKTPFS VL ofSEQ ID NO.: 63 S4-12 SEQ ID NO.: 64 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASARHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYKTPFTFGQGTKLEIKR S4-12 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 64 S4-12 CDR-L2 Residues 50-56 WASARHT VL of SEQ ID NO.: 64 S4-12CDR-L3 Residues 89-97 QQHYKTPFT VL of SEQ ID NO.: 64 S4-74 SEQ ID NO.:65 DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFTFGQGTKLEIKR S4-74 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 65 S4-74 CDR-L2 Residues 50-56WASARHT VL of SEQ ID NO.: 65 S4-74 CDR-L3 Residues 89-97 QQHYRTPFT VL ofSEQ ID NO.: 65 S4-34 SEQ ID NO.: 66 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASTRHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFTFGQGTKLEIKR S4-34 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 66 S4-34 CDR-L2 Residues 50-56 WASTRHT VL of SEQ ID NO.: 66 S4-34CDR-L3 Residues 89-97 QQHYRTPFT VL of SEQ ID NO.: 66 S4-31 SEQ ID NO.:67 DIQMTQSPSSLSASVGDRVTITCRASQGVS VL SALAWYQQKPGKAPKLLIYWASALHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYSAPFTFGQGTKLEIKR S4-31 CDR-L1 Residues24-34 RASQGVSSALA VL of SEQ ID NO.: 67 S4-31 CDR-L2 Residues 50-56WASALHS VL of SEQ ID NO.: 67 S4-31 CDR-L3 Residues 89-97 QQHYSAPFT VL ofSEQ ID NO.: 67 S4-18 SEQ ID NO.: 68 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASTLHSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSTPFTFGQGTKLEIKR S4-18 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 68 S4-18 CDR-L2 Residues 50-56 WASTLHS VL of SEQ ID NO.: 68 S4-18CDR-L3 Residues 89-97 QQHYSTPFT VL of SEQ ID NO.: 68 S4-6 SEQ ID NO.: 69DIQMTQSPSSLSASVGDRVTITCKASQLVS VL SAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYSTPFTFGQGTKLEIKR S4-6 CDR-L1 Residues24-34 KASQLVSSAVA VL of SEQ ID NO.: 69 S4-6 CDR-L2 Residues 50-56WASTRHT VL of SEQ ID NO.: 69 S4-6 CDR-L3 Residues 89-97 QQHYSTPFT VL ofSEQ ID NO.: 69 S4-55 SEQ ID NO.: 70 DIQMTQSPSSLSASVGDRVTITCKASQLVS VLSAVAWYQQKPGKAPKLLIYWASTLHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFTFGQGTKLEIKR S4-55 CDR-L1 Residues 24-34 KASQLVSSAVA VL of SEQ IDNO.: 70 S4-55 CDR-L2 Residues 50-56 WASTLHT VL of SEQ ID NO.: 70 S4-55CDR-L3 Residues 89-97 QQHYRTPFT VL of SEQ ID NO.: 70 S4-63 SEQ ID NO.:71 DIQMTQSPSSLSASVGDRVTITCKASQKVS VL SALAWYQQKPGKAPKLLIYWASALHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRPPFTFGQGTKLEIKR S4-63 CDR-L1 Residues24-34 KASQKVSSALA VL of SEQ ID NO.: 71 S4-63 CDR-L2 Residues 50-56WASALHS VL of SEQ ID NO.: 71 S4-63 CDR-L3 Residues 89-97 QQHYRPPFT VL ofSEQ ID NO.: 71 S4-50 SEQ ID NO.: 72 DIQMTQSPSSLSASVGDRVTITCKASQLVS VLSAVAWYQQKPGKAPKLLIYWASALHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSSPYTFGQGTKLEIKR S4-50 CDR-L1 Residues 24-34 KASQLVSSAVA VL of SEQ IDNO.: 72 S4-50 CDR-L2 Residues 50-56 WASALHT VL of SEQ ID NO.: 72 S4-50CDR-L3 Residues 89-97 QQHYSSPYT VL of SEQ ID NO.: 72 S4-19 SEQ ID NO.:73 DIQMTQSPSSLSASVGDRVTITCKASQLVS VL SAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFTFGQGTKLEIKR S4-19 CDR-L1 Residues24-34 KASQLVSSAVA VL of SEQ ID NO.: 73 S4-19 CDR-L2 Residues 50-56WASTLHT VL of SEQ ID NO.: 73 S4-19 CDR-L3 Residues 89-97 QQHYRTPFT VL ofSEQ ID NO.: 73

C. Individual hMAK-199 Sequences from Converted Clones

Table 8 provides VH sequences of humanized anti-TNF MAK-199 convertedclones as discussed in detail in Example 3.

TABLE 8 Humanized Anti-TNF MAK-199 Ab VH sequences of IgG convertedclones Sequence Protein region 123456789012345678901234567890 J662M2S3SEQ ID NO.: 74 EVQLVQSGAEVKKPGASVKVSCKASGYTFA #10 VHNYGIIWVRQAPGQGLEWMGWINTYTGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFTTMDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 10 VH of SEQ ID NO.: 74 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKFQG 10 VH of SEQ ID NO.: 74 J662M2S3# CDR-H3 Residues99-112 RASQDISQYLN 10 VH of SEQ ID NO.: 74 J662M2S3# SEQ ID NO.: 75EVQLVQSGAEVKKPGASVKVSCKASGYTFN 13 VH NYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKLQGRVTMTTDTSTSTAYMELSSLRSED TAVYFCARKLFNTVDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 13 VH of SEQ ID NO.: 75 J662M2S3#CDR-H2 Residues 50-66 WINTYTGKPTYAQKLQG 13 VH of SEQ ID NO.: 75J662M2S3# CDR-H3 Residues 99-112 KLFNTVDVTDNAMD 13 VH of SEQ ID NO.: 75J662M2S3# SEQ ID NO.: 76 EVQLVQSGAEVKKPGASVKVSCKASGYTFN 15 VHNYGIIWVRQAPGQGLEWMGWINTYTGVPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFNTVDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 15 VH of SEQ ID NO.: 76 J662M2S3# CDR-H2 Residues 50-66WINTYTGVPTYAQKFQG 15 VH of SEQ ID NO.: 76 J662M2S3# CDR-H3 Residues99-112 KLFNTVDVTDNAMD 15 VH of SEQ ID NO.: 76 J662M2S3# SEQ ID NO.: 77EVQLVQSGAEVKKPGASVKVSCKASGYTFN 16 VH NYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYYCARKLFNTVAVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 16 VH of SEQ ID NO.: 77 J662M2S3#CDR-H2 Residues 50-66 WINTYTGKPTYAQKFQG 16 VH of SEQ ID NO.: 77J662M2S3# CDR-H3 Residues 99-112 KLFNTVAVTDNAMD 16 VH of SEQ ID NO.: 77J662M2S3# SEQ ID NO.: 78 EVQLVQSGAEVKKPGASVKVSCKASGYTFR 21 VHNYGIIWVRQAPGQGLEWMGWINTYTGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTTVDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 21 VH of SEQ ID NO.: 78 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKFQG 21 VH of SEQ ID NO.: 78 J662M2S3# CDR-H3 Residues99-112 KLFTTVDVTDNAMD 21 VH of SEQ ID NO.: 78 J662M2S3# SEQ ID NO.: 79EVQLVQSGAEVKKPGASVKVSCKASGYTFN 34 VH NYGINWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYFCARKFRNTVAVTDYAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGIN 34 VH of SEQ ID NO.: 79 J662M2S3#CDR-H2 Residues 50-66 WINTYTGKPTYAQKFQG 34 VH of SEQ ID NO.: 79J662M2S3# CDR-H3 Residues 99-112 KFRNTVAVTDYAMD 34 VH of SEQ ID NO.: 79J662M2S3# SEQ ID NO.: 80 EVQLVQSGAEVKKPGASVKVSCKASGYTFR 36 VHNYGITWVRQAPGQGLEWMGWINTYTGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTTMDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGIT 36 VH of SEQ ID NO.: 80 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKFQG 36 VH of SEQ ID NO.: 80 J662M2S3# CDR-H3 Residues99-112 KLFTTMDVTDNAMD 36 VH of SEQ ID NO.: 80 J662M2S3# SEQ ID NO.: 81EVQLVQSGAEVKKPGASVKVSCKASGYTFA 45 VH NYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYYCARKLFTTMDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 45 VH of SEQ ID NO.: 81 J662M2S3#CDR-H2 Residues 50-66 WINTYTGKPTYAQKFQG 45 VH of SEQ ID NO.: 81J662M2S3# CDR-H3 Residues 99-112 KLFTTMDVTDNAMD 45 VH of SEQ ID NO.: 81J662M2S3# SEQ ID NO.: 82 EVQLVQSGAEVKKPGASVKVSCKASGYTFS 58 VHNYGINWVRQAPGQGLEWMGWINTYTGQPSY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFKTEAVTDYAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGIN 58 VH of SEQ ID NO.: 82 J662M2S3# CDR-H2 Residues 50-66WINTYTGQPSYAQKFQG 58 VH of SEQ ID NO.: 82 J662M2S3# CDR-H3 Residues99-112 KLFKTEAVTDYAMD 58 VH of SEQ ID NO.: 82 J662M2S3# SEQ ID NO.: 83EVQLVQSGAEVKKPGASVKVSCKASGYTFN 72 VH NYGIIWVRQAPGQGLEWMGWINTYSGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYFCARKLFTTMDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 72 VH of SEQ ID NO.: 83 J662M2S3#CDR-H2 Residues 50-66 WINTYSGKPTYAQKFQG 72 VH of SEQ ID NO.: 83J662M2S3# CDR-H3 Residues 99-112 KLFTTMDVTDNAMD 72 VH of SEQ ID NO.: 83

Table 9 provides VL sequences of humanized anti-TNF MAK-199 convertedclones as discussed in detail in Example 3.

TABLE 9 Humanized Anti-TNF MAK-199 Ab VL sequences of IgG convertedclones Sequence Protein region 123456789012345678901234567890 J662M2S3#SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIS 10 VL NO.: 84QYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYFCQQGNTWPPTFGQGTKLEIK J662M2S3#10 CDR-L1 Residues 24-34 RASQDISQYLN VL ofSEQ ID NO.: 84 J662M2S3#10 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 84 J662M2S3#10 CDR-L3 Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 84J662M2S3#13 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NO.: 85NYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNSWPPTFGQGTKLEIK J662M2S3#13 CDR-L1 Residues 24-34 RASQDISNYLN VL ofSEQ ID NO.: 85 J662M2S3#13 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 85 J662M2S3#13 CDR-L3 Residues 89-97 QQGNSWPPT VL of SEQ ID NO.: 85J662M2S3#15 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIY VL NO.: 86NYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTQPPTFGQGTKLEIK J662M2S3#15 CDR-L1 Residues 24-34 RASQDIYNYLN VL ofSEQ ID NO.: 86 J662M2S3#15 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 86 J662M2S3#15 CDR-L3 Residues 89-97 QQGNTQPPT VL of SEQ ID NO.: 86J662M2S3#16 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIE VL NO.: 87NYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYFCQQGNTQPPTFGQGTKLEIK J662M2S3#16 CDR-L1 Residues 24-34 RASQDIENYLN VL ofSEQ ID NO.: 87 J662M2S3#16 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 87 J662M2S3#16 CDR-L3 Residues 89-97 QQGNTQPPT VL of SEQ ID NO.: 87J662M2S3#21 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NO.: 88NYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTWPPTFGQGTKLEIK J662M2S3#21 CDR-L1 Residues 24-34 RASQDISNYLN VL ofSEQ ID NO.: 88 J662M2S3#21 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 88 J662M2S3#21 CDR-L3 Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 88J662M2S3#34 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIY VL NO.: 89DVLNWYQQKPGKAPKLLIYYASRLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQGITLPPTFGQGTKLEIK J662M2S3#34 CDR-L1 Residues 24-34 RASQDIYDVLN VL ofSEQ ID NO.: 89 J662M2S3#34 CDR-L2 Residues 50-56 YASRLQS VL of SEQ IDNO.: 89 J662M2S3#34 CDR-L3 Residues 89-97 QQGITLPPT VL of SEQ ID NO.: 89J662M2S3#36 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NO.: 90NYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTWPPTFGQGTKLEIK J662M2S3#36 CDR-L1 Residues 24-34 RASQDISNYLN VL ofSEQ ID NO.: 90 J662M2S3#36 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 90 J662M2S3#36 CDR-L3 Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 90J662M2S3#45 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NO.: 91QYLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYFCQQGNTWPPTFGQGTKLEIK J662M2S3#45 CDR-L1 Residues 24-34 RASQDISQYLN VL ofSEQ ID NO.: 91 J662M2S3#45 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 91 J662M2S3#45 CDR-L3 Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 91J662M2S3#58 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQNIY VL NO.: 92NVLNWYQQKPGKAPKLLIYYASRLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYFCQQGNTMPPTFGQGTKLEIK J662M2S3#58 CDR-L1 Residues 24-34 RASQNIYNVLN VL ofSEQ ID NO.: 92 J662M2S3#58 CDR-L2 Residues 50-56 YASRLQS VL of SEQ IDNO.: 92 J662M2S3#58 CDR-L3 Residues 89-97 QQGNTMPPT VL of SEQ ID NO.: 92J662M2S3#72 SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NO.: 93NFLNWYQQKPGKAPKLLIYYTSRLQSGVPS RFSGSGSGTDYTLTISSLQPEDFATYFCQQGNTQPPTFGQGTKLEIK J662M2S3#72 CDR-L1 Residues 24-34 RASQDISNFLN VL ofSEQ ID NO.: 93 J662M2S3#72 CDR-L2 Residues 50-56 YTSRLQS VL of SEQ IDNO.: 93 J662M2S3#72 CDR-L3 Residues 89-97 QQGNTQPPT VL of SEQ ID NO.: 93

In an embodiment, the antigen binding domain comprises the VH regionchosen from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, 34-58, 74-83,94-266, 478-486, 496-675, 738-762, 778-956, 1053-1062, 1073, 1075, and1077, or one, two, or three CDRs therefrom. In another embodiment, theantigen binding domain comprises the VL region chosen from any one ofSEQ ID NOs: 23, 25, 27, 29, 31, 33, 59-73, 84-93, 267-477, 487-495,676-737, 763-777, 957-1052, 1063-1072, 1074, 1076, and 1078, or one,two, or three CDRs therefrom. In a particular embodiment, the antigenbinding domain comprises a VH region and a VL region, for example,wherein the VH region comprises SEQ ID NOs: 22, 24, 26, 28, 30, 32,34-58, 74-83, 94-266, 478-486, 496-675, 738-762, 778-956, 1053-1062,1073, 1075, and 1077, or one, two, or three CDRs therefrom, and the VLregion comprises SEQ ID NOs: 23, 25, 27, 29, 31, 33, 59-73, 84-93,267-477, 487-495, 676-737, 763-777, 957-1052, 1063-1072, 1074, 1076, and1078, or one, two, or three CDRs therefrom.

In an embodiment where the VH and/or the VL CDR sequences are providedabove, the human acceptor framework comprises at least one amino acidsequence selected from: SEQ ID NOs: 6-21. In a particular embodiment,the human acceptor framework comprises an amino acid sequence selectedfrom: SEQ 1N NOs: 9, 10, 11, 12, 15, 16, 17, and 21. In anotherembodiment, the human acceptor framework comprises at least oneframework region amino acid substitution, wherein the amino acidsequence of the framework is at least 65% identical to the sequence ofthe human acceptor framework and comprises at least 70 amino acidresidues identical to the human acceptor framework. In anotherembodiment, the human acceptor framework comprises at least oneframework region amino acid substitution at a key residue. The keyresidue selected from: a residue adjacent to a CDR; a glycosylation siteresidue; a rare residue; a residue capable of interacting with humanTNF-α; a residue capable of interacting with a CDR; a canonical residue;a contact residue between heavy chain variable region and light chainvariable region; a residue within a Vernier zone; and a residue in aregion that overlaps between a Chothia-defined variable heavy chain CDR1and a Kabat-defined first heavy chain framework. In an embodiment, thekey residue is selected from: H1, H12, H24, H27, H29, H37, H48, H49,H67, H71, H73, H76, H78, L13, L43, L58, L70, and L80. In an embodiment,the VH mutation is selected from: Q1E, I12V, A24V, G27F, I29L, V29F F29L137V, I48L, V48L, S49G, V67L, F67L, V71K, R71K, T73N, N76S, L78I, andF78I. In another embodiment, the VL mutation is selected from: V13L,A435, I58V, E70D, and S80P. In an embodiment, the binding proteincomprises two variable domains, wherein the two variable domains haveamino acid sequences selected from: SEQ ID NOS: 22 and 23; 23 and 24; 24and 25; 26 and 27; 28 and 29; 30 and 31; or 32 and 33.

III. Production of Binding Proteins and Binding Protein-Producing CellLines

In an embodiment, TNF-α binding proteins disclosed herein exhibit a highcapacity to reduce or to neutralize TNF-α activity, e.g., as assessed byany one of several in vitro and in vivo assays known in the art.Alternatively, TNF-α binding proteins disclosed herein, also exhibit ahigh capacity to increase or agonize TNF-α activity.

In particular embodiments, the isolated binding protein, orantigen-binding portion thereof, binds human TNF-α, wherein the bindingprotein, or antigen-binding portion thereof, dissociates from humanTNF-α with a k_(off) rate constant of about 0.1 s⁻¹ or less, asdetermined by surface plasmon resonance, such as 1×10⁻² s⁻¹ or less,1×10⁻³ s⁻¹ or less, 1×10⁻⁴ s⁻¹ or less, 1×10⁻⁵ s⁻¹ or less and 1×10⁻⁶s⁻¹ or less; or which inhibits human TNF-α activity with an IC₅₀ ofabout 1×10⁻⁶ M or less, such as 1×10⁻⁷M or less, 1×10⁻⁸M or less,1×10⁻⁹M or less, 1×10−10 M or less and 1×10¹¹ M or less. In certainembodiments, the binding protein comprises a heavy chain constantregion, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constantregion. In an embodiment, the heavy chain constant region is an IgG1heavy chain constant region or an IgG4 heavy chain constant region.Furthermore, the binding protein can comprise a light chain constantregion, either a kappa light chain constant region or a lambda lightchain constant region. In another embodiment, the binding proteincomprises a kappa light chain constant region. Alternatively, thebinding protein portion can be, for example, a Fab fragment or a singlechain Fv fragment.

Replacements of amino acid residues in the Fc portion to alter bindingprotein effector function are known in the art (See U.S. Pat. Nos.5,648,260 and 5,624,821). The Fc portion of a binding protein mediatesseveral important effector functions, e.g., cytokine induction, ADCC,phagocytosis, complement dependent cytotoxicity (CDC) andhalf-life/clearance rate of antibody and antigen-antibody complexes. Insome cases these effector functions are desirable for therapeuticantibody but in other cases might be unnecessary or even deleterious,depending on the therapeutic objectives. Certain human IgG isotypes,particularly IgG1 and IgG3, mediate ADCC and CDC via binding to FcγRsand complement C1q, respectively. Neonatal Fc receptors (FcRn) are thecritical components determining the circulating half-life of antibodies.In still another embodiment at least one amino acid residue is replacedin the constant region of the binding protein, for example the Fc regionof the binding protein, such that effector functions of the bindingprotein are altered.

One embodiment provides a labeled binding protein wherein an antibody orantibody portion disclosed herein is derivatized or linked to anotherfunctional molecule (e.g., another peptide or protein). For example, alabeled binding protein disclosed herein can be derived by functionallylinking an antibody or antibody portion disclosed herein (by chemicalcoupling, genetic fusion, noncovalent association or otherwise) to oneor more other molecular entities, such as another antibody (e.g., abispecific antibody or a diabody), a detectable agent, a cytotoxicagent, a pharmaceutical agent, and/or a protein or peptide that canmediate associate of the antibody or antibody portion with anothermolecule (such as a streptavidin core region or a polyhistidine tag).

Useful detectable agents with which an antibody or antibody portiondisclosed herein may be derivatized include fluorescent compounds.Exemplary fluorescent detectable agents include fluorescein, fluoresceinisothiocyanate, rhodamine, 5-dimethylamine-1-napthalenesulfonylchloride, phycoerythrin and the like. An antibody may also bederivatized with detectable enzymes, such as alkaline phosphatase,horseradish peroxidase, glucose oxidase and the like. When an antibodyis derivatized with a detectable enzyme, it is detected by addingadditional reagents that the enzyme uses to produce a detectablereaction product. For example, when the detectable agent horseradishperoxidase is present, the addition of hydrogen peroxide anddiaminobenzidine leads to a colored reaction product, which isdetectable. An antibody may also be derivatized with biotin, anddetected through indirect measurement of avidin or streptavidin binding.

Another embodiment of the disclosure provides a crystallized bindingprotein. In an embodiment, provided are crystals of whole TNF-α bindingproteins and fragments thereof as disclosed herein, and formulations andcompositions comprising such crystals. In one embodiment thecrystallized binding protein has a greater half-life in vivo than thesoluble counterpart of the binding protein. In another embodiment thebinding protein retains biological activity after crystallization.

Crystallized binding protein disclosed herein may be produced accordingmethods known in the art and as disclosed in PCT Publication WO02/72636.

Another embodiment of the disclosure provides a glycosylated bindingprotein wherein the binding protein or antigen-binding portion thereofcomprises one or more carbohydrate residues. Nascent in vivo proteinproduction may undergo further processing, known as post-translationalmodification. In particular, sugar (glycosyl) residues may be addedenzymatically, a process known as glycosylation. The resulting proteinsbearing covalently linked oligosaccharide side chains are known asglycosylated proteins or glycoproteins. Protein glycosylation depends onthe amino acid sequence of the protein of interest, as well as the hostcell in which the protein is expressed. Different organisms may producedifferent glycosylation enzymes (e.g., glycosyltransferases andglycosidases), and have different substrates (nucleotide sugars)available. Due to such factors, protein glycosylation pattern, andcomposition of glycosyl residues, may differ depending on the hostsystem in which the particular protein is expressed. Glycosyl residuesuseful in the disclosure may include, but are not limited to, glucose,galactose, mannose, fucose, n-acetylglucosamine and sialic acid. In anembodiment, the glycosylated binding protein comprises glycosyl residuessuch that the glycosylation pattern is human.

It is known to those skilled in the art that differing proteinglycosylation may result in differing protein characteristics. Forinstance, the efficacy of a therapeutic protein produced in amicroorganism host, such as yeast, and glycosylated utilizing the yeastendogenous pathway may be reduced compared to that of the same proteinexpressed in a mammalian cell, such as a CHO cell line. Suchglycoproteins may also be immunogenic in humans and show reducedhalf-life in vivo after administration. Specific receptors in humans andother animals may recognize specific glycosyl residues and promote therapid clearance of the protein from the bloodstream. Other adverseeffects may include changes in protein folding, solubility,susceptibility to proteases, trafficking, transport,compartmentalization, secretion, recognition by other proteins orfactors, antigenicity, or allergenicity. Accordingly, a practitioner mayprefer a therapeutic protein with a specific composition and pattern ofglycosylation, for example glycosylation composition and patternidentical, or at least similar, to that produced in human cells or inthe species-specific cells of the intended subject animal.

Expressing glycosylated proteins different from that of a host cell maybe achieved by genetically modifying the host cell to expressheterologous glycosylation enzymes. Using techniques known in the art apractitioner may generate antibodies or antigen-binding portions thereofexhibiting human protein glycosylation. For example, yeast strains havebeen genetically modified to express non-naturally occurringglycosylation enzymes such that glycosylated proteins (glycoproteins)produced in these yeast strains exhibit protein glycosylation identicalto that of animal cells, especially human cells (U.S. Pat. Nos.7,449,308 and 7,029,872).

Further, it will be appreciated by one skilled in the art that a proteinof interest may be expressed using a library of host cells geneticallyengineered to express various glycosylation enzymes, such that memberhost cells of the library produce the protein of interest with variantglycosylation patterns. A practitioner may then select and isolate theprotein of interest with particular novel glycosylation patterns. In anembodiment, the protein having a particularly selected novelglycosylation pattern exhibits improved or altered biologicalproperties.

IV. Uses of TNF-α Binding Proteins

Given their ability to bind to human TNF-α, e.g., the human TNF-αbinding proteins, or portions thereof, disclosed herein can be used todetect TNF-α (e.g., in a biological sample, such as serum or plasma),using a conventional immunoassay, such as an enzyme linked immunosorbentassays (ELISA), an radioimmunoassay (RIA) or tissueimmunohistochemistry. A method for detecting TNF-α in a biologicalsample is provided comprising contacting a biological sample with abinding protein, or binding protein portion, disclosed herein anddetecting either the binding protein (or binding protein portion) boundto TNF-α or unbound binding protein (or binding protein portion), tothereby detect TNF-α in the biological sample. The binding protein isdirectly or indirectly labeled with a detectable substance to facilitatedetection of the bound or unbound antibody. Suitable detectablesubstances include various enzymes, prosthetic groups, fluorescentmaterials, luminescent materials and radioactive materials. Examples ofsuitable enzymes include horseradish peroxidase, alkaline phosphatase,β-galactosidase, or acetylcholinesterase; examples of suitableprosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; and examples ofsuitable radioactive material include ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In,¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, or ¹⁵³Sm.

Alternative to labeling the binding protein, human TNF-α can be assayedin biological fluids by a competition immunoassay utilizing rhTNF-αstandards labeled with a detectable substance and an unlabeled humanTNF-α binding protein. In this assay, the biological sample, the labeledrhTNF-α standards and the human TNF-α binding protein are combined andthe amount of labeled rhTNF-α standard bound to the unlabeled bindingprotein is determined. The amount of human TNF-α in the biologicalsample is inversely proportional to the amount of labeled rhTNF-αstandard bound to the TNF-α binding protein. Similarly, human TNF-α canalso be assayed in biological fluids by a competition immunoassayutilizing rhTNF-α standards labeled with a detectable substance and anunlabeled human TNF-α binding protein.

In an embodiment, the binding proteins and binding protein portionsdisclosed herein are capable of neutralizing TNF-α activity, e.g., humanTNF-α activity, both in vitro and in vivo. In another embodiment, thebinding proteins and binding protein portions disclosed herein arecapable of increasing or agonizing human TNF-α activity, e.g., humanTNF-α activity. Accordingly, such binding proteins and binding proteinportions disclosed herein can be used to inhibit or increase hTNF-αactivity, e.g., in a cell culture containing hTNF-α, in human subjectsor in other mammalian subjects having TNF-α with which a binding proteindisclosed herein cross-reacts. In one embodiment, a method forinhibiting or increasing hTNF-α activity is provided comprisingcontacting hTNF-α with a binding protein or binding protein portiondisclosed herein such that hTNF-α activity is inhibited or increased.For example, in a cell culture containing, or suspected of containinghTNF-α, a binding protein or binding protein portion disclosed hereincan be added to the culture medium to inhibit or increase hTNF-αactivity in the culture.

In another embodiment, a method is provided for reducing or increasinghTNF-α activity in a subject, advantageously from a subject sufferingfrom a disease or disorder in which TNF-α activity is detrimental or,alternatively, beneficial. Methods for reducing or increasing TNF-αactivity in a subject suffering from such a disease or disorder isprovided, which method comprises administering to the subject a bindingprotein or binding protein portion disclosed herein such that TNF-αactivity in the subject is reduced or increased. In a particularembodiment, the TNF-α is human TNF-α, and the subject is a humansubject. Alternatively, the subject can be a mammal expressing a TNF-αto which a binding protein provided is capable of binding. Still furtherthe subject can be a mammal into which TNF-α has been introduced (e.g.,by administration of TNF-α or by expression of a TNF-α transgene). Abinding protein disclosed herein can be administered to a human subjectfor therapeutic purposes. Moreover, a binding protein disclosed hereincan be administered to a non-human mammal expressing a TNF-α with whichthe binding protein is capable of binding for veterinary purposes or asan animal model of human disease. Regarding the latter, such animalmodels may be useful for evaluating the therapeutic efficacy of bindingproteins disclosed herein (e.g., testing of dosages and time courses ofadministration).

The term “a disorder in which TNF-α activity is detrimental” includesdiseases and other disorders in which the presence of TNF-α activity ina subject suffering from the disorder has been shown to be or issuspected of being either responsible for the pathophysiology of thedisorder or a factor that contributes to a worsening of the disorder.Accordingly, a disorder in which TNF-α activity is detrimental is adisorder in which reduction of TNF-α activity is expected to alleviatethe symptoms and/or progression of the disorder. Such disorders may beevidenced, for example, by an increase in the concentration of TNF-α ina biological fluid of a subject suffering from the disorder (e.g., anincrease in the concentration of TNF-α in serum, plasma, synovial fluid,etc. of the subject), which can be detected, for example, using ananti-TNF-α antibody as described above. Non-limiting examples ofdisorders that can be treated with the binding proteins disclosed hereininclude those disorders discussed in the section below pertaining topharmaceutical compositions of the antibodies disclosed herein.

Alternatively, the term “a disorder in which TNF-α activity isbeneficial” include diseases and other disorders in which the presenceof TNF-α activity in a subject suffering from the disorder has beenshown to be or is suspected of being either beneficial for treating thepathophysiology of the disorder or a factor that contributes to atreatment of the disorder. Accordingly, a disorder in which TNF-αactivity is beneficial is a disorder in which an increase of TNF-αactivity is expected to alleviate the symptoms and/or progression of thedisorder. Non-limiting examples of disorders that can be treated withthe antibodies disclosed herein include those disorders discussed in thesection below pertaining to pharmaceutical compositions of theantibodies disclosed herein.

V. Pharmaceutical Compositions

Pharmaceutical compositions are also provided comprising a bindingprotein, or antigen-binding portion thereof, disclosed herein and apharmaceutically acceptable carrier. The pharmaceutical compositionscomprising binding protein disclosed herein are for use in, but notlimited to, diagnosing, detecting, or monitoring a disorder, inpreventing, treating, managing, or ameliorating of a disorder or one ormore symptoms thereof, and/or in research. In a specific embodiment, acomposition comprises one or more binding proteins disclosed herein. Inanother embodiment, the pharmaceutical composition comprises one or morebinding proteins disclosed herein and one or more prophylactic ortherapeutic agents other than binding proteins disclosed herein fortreating a disorder in which TNF-α activity is detrimental. In aparticular embodiment, the prophylactic or therapeutic agents known tobe useful for or having been or currently being used in the prevention,treatment, management, or amelioration of a disorder or one or moresymptoms thereof. In accordance with these embodiments, the compositionmay further comprise of a carrier, diluent or excipient.

The binding proteins and binding protein-portions disclosed herein canbe incorporated into pharmaceutical compositions suitable foradministration to a subject. Typically, the pharmaceutical compositioncomprises a binding protein or binding protein portion disclosed hereinand a pharmaceutically acceptable carrier. The term “pharmaceuticallyacceptable carrier” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like that are physiologically compatible.Examples of pharmaceutically acceptable carriers include one or more ofwater, saline, phosphate buffered saline, dextrose, glycerol, ethanoland the like, as well as combinations thereof. In many cases, isotonicagents, for example, sugars, polyalcohols such as mannitol, sorbitol, orsodium chloride in the composition, may be included. Pharmaceuticallyacceptable carriers may further comprise minor amounts of auxiliarysubstances such as wetting or emulsifying agents, preservatives orbuffers, which enhance the shelf life or effectiveness of the bindingprotein or binding protein portion.

Various delivery systems are known and can be used to administer one ormore binding proteins disclosed herein or the combination of one or morebinding proteins disclosed herein and a prophylactic agent ortherapeutic agent useful for preventing, managing, treating, orameliorating a disorder or one or more symptoms thereof, e.g.,encapsulation in liposomes, microparticles, microcapsules, recombinantcells capable of expressing the binding protein or binding proteinfragment, receptor-mediated endocytosis (see, e.g., Wu and Wu (1987) J.Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of aretroviral or other vector, etc. Methods of administering a prophylacticor therapeutic agent disclosed herein include, but are not limited to,parenteral administration (e.g., intradermal, intramuscular,intraperitoneal, intravenous and subcutaneous), epidural administration,intratumoral administration, and mucosal administration (e.g.,intranasal and oral routes). In addition, pulmonary administration canbe employed, e.g., by use of an inhaler or nebulizer, and formulationwith an aerosolizing agent. In one embodiment, a binding proteindisclosed herein, combination therapy, or a composition disclosed hereinis administered using Alkermes AIR® pulmonary drug delivery technology(Alkermes, Inc., Cambridge, Mass.). In a specific embodiment,prophylactic or therapeutic agents disclosed herein are administeredintramuscularly, intravenously, intratumorally, orally, intranasally,pulmonary, or subcutaneously. The prophylactic or therapeutic agents maybe administered by any convenient route, for example by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and maybe administered together with other biologically active agentsAdministration can be systemic or local.

In a specific embodiment, it may be desirable to administer theprophylactic or therapeutic agents disclosed herein locally to the areain need of treatment; this may be achieved by, for example, and not byway of limitation, local infusion, by injection, or by means of animplant, said implant being of a porous or non-porous material,including membranes and matrices, such as sialastic membranes, polymers,fibrous matrices (e.g., Tissuel®), or collagen matrices. In oneembodiment, an effective amount of one or more binding proteinsdisclosed herein antagonists is administered locally to the affectedarea to a subject to prevent, treat, manage, and/or ameliorate adisorder or a symptom thereof. In another embodiment, an effectiveamount of one or more binding proteins disclosed herein is administeredlocally to the affected area in combination with an effective amount ofone or more therapies (e.g., one or more prophylactic or therapeuticagents) other than an antibody disclosed herein of a subject to prevent,treat, manage, and/or ameliorate a disorder or one or more symptomsthereof.

In a specific embodiment, where the composition disclosed herein is anucleic acid encoding a prophylactic or therapeutic agent, the nucleicacid can be administered in vivo to promote expression of its encodedprophylactic or therapeutic agent, by constructing it as part of anappropriate nucleic acid expression vector and administering it so thatit becomes intracellular, e.g., by use of a retroviral vector (see U.S.Pat. No. 4,980,286), or by direct injection, or by use of microparticlebombardment (e.g., a gene gun; Biolistic, DuPont), or coating withlipids or cell-surface receptors or transfecting agents, or byadministering it in linkage to a homeobox-like peptide which is known toenter the nucleus (see, e.g., Joliot et al. (1991) Proc. Natl. Acad.Sci. USA 88:1864-1868). Alternatively, a nucleic acid can be introducedintracellularly and incorporated within host cell DNA for expression byhomologous recombination.

The method disclosed herein may comprise administration of a compositionformulated for parenteral administration by injection (e.g., by bolusinjection or continuous infusion). Formulations for injection may bepresented in unit dosage form (e.g., in ampoules or in multi-dosecontainers) with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle (e.g., sterile pyrogen-free water) before use.

The methods disclosed herein may additionally comprise of administrationof compositions formulated as depot preparations. Such long actingformulations may be administered by implantation (e.g., subcutaneouslyor intramuscularly) or by intramuscular injection. Thus, for example,the compositions may be formulated with suitable polymeric orhydrophobic materials (e.g., as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives (e.g., as asparingly soluble salt).

The methods disclosed herein encompass administration of compositionsformulated as neutral or salt forms. Pharmaceutically acceptable saltsinclude those formed with anions such as those derived fromhydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., andthose formed with cations such as those derived from sodium, potassium,ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine,2-ethylamino ethanol, histidine, procaine, etc.

Generally, the ingredients of compositions are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the mode of administration is infusion, compositioncan be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the mode of administrationis by injection, an ampoule of sterile water for injection or saline canbe provided so that the ingredients may be mixed prior toadministration.

In particular, it is also provided that one or more of the prophylacticor therapeutic agents, or pharmaceutical compositions disclosed hereinis packaged in a hermetically sealed container such as an ampoule orsachette indicating the quantity of the agent. In one embodiment, one ormore of the prophylactic or therapeutic agents, or pharmaceuticalcompositions disclosed herein is supplied as a dry sterilizedlyophilized powder or water free concentrate in a hermetically sealedcontainer and can be reconstituted (e.g., with water or saline) to theappropriate concentration for administration to a subject. In anembodiment, one or more of the prophylactic or therapeutic agents orpharmaceutical compositions disclosed herein is supplied as a drysterile lyophilized powder in a hermetically sealed container at a unitdosage of at least 5 mg, at least 10 mg, at least 15 mg, at least 25 mg,at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or atleast 100 mg. The lyophilized prophylactic or therapeutic agents orpharmaceutical compositions disclosed herein should be stored at between2° C. and 8° C. in its original container and the prophylactic ortherapeutic agents, or pharmaceutical compositions disclosed hereinshould be administered within 1 week, within 5 days, within 72 hours,within 48 hours, within 24 hours, within 12 hours, within 6 hours,within 5 hours, within 3 hours, or within 1 hour after beingreconstituted. In an alternative embodiment, one or more of theprophylactic or therapeutic agents or pharmaceutical compositionsdisclosed herein is supplied in liquid form in a hermetically sealedcontainer indicating the quantity and concentration of the agent. In anembodiment, the liquid form of the administered composition is suppliedin a hermetically sealed container at least 0.25 mg/ml, at least 0.5mg/ml, at least 1 mg/ml, at least 2.5 mg/ml, at least 5 mg/ml, at least8 mg/ml, at least 10 mg/ml, at least 15 mg/kg, at least 25 mg/ml, atleast 50 mg/ml, at least 75 mg/ml or at least 100 mg/ml. The liquid formshould be stored at between 2° C. and 8° C. in its original container.

The binding proteins and binding protein-portions disclosed herein canbe incorporated into a pharmaceutical composition suitable forparenteral administration. In an embodiment, the binding protein orbinding protein-portions will be prepared as an injectable solutioncontaining 0.1-250 mg/ml binding protein. The injectable solution can becomposed of either a liquid or lyophilized dosage form in a flint oramber vial, ampoule or pre-filled syringe. The buffer can be L-histidine(1-50 mM), optimally 5-10 mM, at pH 5.0 to 7.0 (optimally pH 6.0). Othersuitable buffers include but are not limited to, sodium succinate,sodium citrate, sodium phosphate or potassium phosphate. Sodium chloridecan be used to modify the toxicity of the solution at a concentration of0-300 mM (optimally 150 mM for a liquid dosage form). Cryoprotectantscan be included for a lyophilized dosage form, principally 0-10% sucrose(optimally 0.5-1.0%). Other suitable cryoprotectants include trehaloseand lactose. Bulking agents can be included for a lyophilized dosageform, principally 1-10% mannitol (optimally 2-4%). Stabilizers can beused in both liquid and lyophilized dosage forms, principally 1-50 mML-Methionine (optimally 5-10 mM). Other suitable bulking agents includeglycine, arginine, can be included as 0-0.05% polysorbate-80 (optimally0.005-0.01%). Additional surfactants include but are not limited topolysorbate 20 and BRIJ surfactants.

Typical compositions are in the form of injectable or infusiblesolutions, such as compositions similar to those used for passiveimmunization of humans with other antibodies. Therapeutic compositionstypically must be sterile and stable under the conditions of manufactureand storage. The composition can be formulated as a solution,microemulsion, dispersion, liposome, or other ordered structure suitableto high drug concentration. Sterile injectable solutions can be preparedby incorporating the active compound (i.e., binding protein or bindingprotein portion) in the required amount in an appropriate solvent withone or a combination of ingredients enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the active compound into a sterile vehicle thatcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile, lyophilized powdersfor the preparation of sterile injectable solutions, the methods ofpreparation include vacuum drying and spray-drying that yields a powderof the active ingredient plus any additional desired ingredient from apreviously sterile-filtered solution thereof. The proper fluidity of asolution can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prolonged absorption ofinjectable compositions can be brought about by including, in thecomposition, an agent that delays absorption, for example, monostearatesalts and gelatin.

As will be appreciated by the skilled artisan, the route and/or mode ofadministration will vary depending upon the desired results. In certainembodiments, the active compound may be prepared with a carrier thatwill protect the compound against rapid release, such as a controlledrelease formulation, including implants, transdermal patches, andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Manymethods for the preparation of such formulations are patented orgenerally known to those skilled in the art. See, e.g., Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978.

Supplementary active compounds can also be incorporated into thecompositions. In certain embodiments, a binding protein or bindingprotein portion disclosed herein is coformulated with and/orcoadministered with one or more additional therapeutic agents that areuseful for treating disorders in which TNF-α activity is detrimental.For example, an anti-hTNF-α antibody or antibody portion disclosedherein may be coformulated and/or coadministered with one or moreadditional antibodies that bind other targets (e.g., antibodies thatbind other cytokines or that bind cell surface molecules). Furthermore,one or more binding proteins disclosed herein may be used in combinationwith two or more of the foregoing therapeutic agents. Such combinationtherapies may advantageously utilize lower dosages of the administeredtherapeutic agents, thus avoiding possible toxicities or complicationsassociated with the various monotherapies.

In certain embodiments, a binding protein to TNF-α or fragment thereofis linked to a half-life extending vehicle known in the art. Suchvehicles include, but are not limited to, the Fc domain, polyethyleneglycol, and dextran. Such vehicles are described, e.g., in U.S. Pat. No.6,660,843.

In a specific embodiment, nucleic acid sequences comprising nucleotidesequences encoding a binding protein disclosed herein or anotherprophylactic or therapeutic agent disclosed herein are administered totreat, prevent, manage, or ameliorate a disorder or one or more symptomsthereof by way of gene therapy. Gene therapy refers to therapy performedby the administration to a subject of an expressed or expressiblenucleic acid. In this embodiment of the disclosure, the nucleic acidsproduce their encoded binding protein or prophylactic or therapeuticagent disclosed herein that mediates a prophylactic or therapeuticeffect.

Any of the methods for gene therapy available in the art can be usedaccording to the present disclosure.

TNF-α plays a critical role in the pathology associated with a varietyof diseases involving immune and inflammatory elements, such asautoimmune diseases, particularly those associated with inflammation,including Crohn's disease, psoriasis (including plaque psoriasis),arthritis (including rheumatoid arthritis, psoratic arthritis,osteoarthritis, or juvenile idiopathic arthritis), multiple sclerosis,systemic lupus erythematosus, and ankylosing spondylitis. Therefore, thebinding proteins herein may be used to treat these disorders. In anotherembodiment, the disorder is a respiratory disorder; asthma; allergic andnonallergic asthma; asthma due to infection; asthma due to infectionwith respiratory syncytial virus (RSV); chronic obstructive pulmonarydisease (COPD); a condition involving airway inflammation; eosinophilia;fibrosis and excess mucus production; cystic fibrosis; pulmonaryfibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema;allergic rhinitis; allergic enterogastritis; an inflammatory and/orautoimmune condition of the skin; an inflammatory and/or autoimmunecondition of gastrointestinal organs; inflammatory bowel diseases (IBD);ulcerative colitis; an inflammatory and/or autoimmune condition of theliver; liver cirrhosis; liver fibrosis; liver fibrosis caused byhepatitis B and/or C virus; scleroderma; tumors or cancers;hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; aviral infection; a bacterial infection; a parasitic infection; HTLV-1infection; suppression of expression of protective type 1 immuneresponses, suppression of expression of a protective type 1 immuneresponse during vaccination, neurodegenerative diseases, neuronalregeneration, and spinal cord injury.

It will be readily apparent to those skilled in the art that othersuitable modifications and adaptations of the methods disclosed hereinmay be made using suitable equivalents without departing from the scopeof the invention or the embodiments disclosed herein. Having nowdescribed the present disclosure in detail, the same will be moreclearly understood by reference to the following examples, which areincluded for purposes of illustration only and are not intended to belimiting of the invention.

EXAMPLES Example 1 Identification of Fully Human Antibodies to TNF by InVitro Display Systems 1.1: Antibody Selections

Fully human anti-human TNF monoclonal antibodies were isolated by invitro display technologies from human antibody libraries by theirability to bind recombinant human TNF proteins. The amino acid sequencesof the variable heavy (VH) and variable light (VL) chains weredetermined from DNA sequencing and listed in Table 10.

TABLE 10 Individual clones sequences Sequence Protein region SEQ ID NO:123456789012345678901234567890 AE11-1 VH 22EVQLVQSGAEVKKPGASVKVSCKASGYTFT SYDVN WVRQATGQGLEWMG WMNPNSGNTGY AQKFQGRVTITADESTSTAYMELSSLRSED TAVYYCAI FDSDYMDV WGKGTLVTVSS AE11-1 VH CDR-Residues 31-35 SYDVN H1 of SEQ ID NO.: 22 AE11-1 VH CDR- Residues 50-66WMNPNSGNTGYAQKFQG H2 of SEQ ID NO.: 22 AE11-1 VH CDR- Residues 99-106FDSDYMDV H3 of SEQ ID NO.: 22 AE11-1 VL 23 SYELTQPPSVSLSPGQTARITCSGDALPKQ YAY WYQQKPGQAPVLVIY KDTERPS GIPER FSGSSSGTTVTLTISGAQAEDEADYYCQSA DSSGTSWV FGGGTKLTVL AE11-1 VL CDR- Residues 23-33 SGDALPKQYAY L1 ofSEQ ID NO.: 23 AE11-1 VL CDR- Residues 49-55 KDTERPS L2 of SEQ ID NO.:23 AE11-1 VL CDR- Residues 89-98 SADSSGTSWV L3 of SEQ ID NO.: 23 AE11-5VH 24 EVQLVQSGAEVKKPGSSAKVSCKASGGTFS SYAIS WVRQAPGQGLEWMG GIIPILGTANYAQKFLG RVTITADESTSTVYMELSSLRSED TAVYYCAR GLYYDPTRADY WGQGTLVTVSS AE11-5VH CDR- Residues 31-35 SYAIS H1 of SEQ ID NO.: 24 AE11-5 VH CDR-Residues 50-66 GIIPILGTANYAQKFLG H2 of SEQ ID NO.: 24 AE11-5 VH CDR-Residues 99-109 GLYYDPTRADY H3 of SEQ ID NO.: 24 AE11-5 VL 25DIVMTQSPDFHSVTPKEKVTITC RASQSIG SSLH WYQQKPDQSPKLLIR HASQSIS GVPSRFSGSGSGTDFTLTIHSLEAEDAATYYC HQ SSSSPPPT FGQGTQVEIK AE11-5 VL CDR-Residues 24-34 RASQSIGSSLH L1 of SEQ ID NO.: 25 AE11-5 VL CDR- Residues50-56 HASQSIS L2 of SEQ ID NO.: 25 AE11-5 VL CDR- Residues 89-98HQSSSSPPPT L3 of SEQ ID NO.: 25 TNF-JK1 VH 26EVQLVESGGGLVQPGGSLRLSCATSGFTFN NYWMS WVRQAPGKGLEWVA NINHDESEKYY VDSAKGRFTISRDNAEKSLFLQMNSLRAED TAVYYCAR IIRGRVGFDYYNYAMDV WGQGT LVTVSS TNF-JK1VH CDR- Residues 31-35 NYWMS H1 of SEQ ID NO.: 26 TNF-JK1 VH CDR-Residues 50-66 NINHDESEKYYVDSAKG H2 of SEQ ID NO.: 26 TNF-JK1 VH CDR-Residues 99-115 IIRGRVGFDYYNYAMDV H3 of SEQ ID NO.: 26 TNF-JK1 VL 27DIRLTQSPSPLSASVGDRVTITC RASQSIG NYLN WYQHKPGKAPKLLIY AASSLQS GVPSRFSGTGSGTDFTLTISSLQPEDFATYYC QE SYSLI FAGGTKVEIK TNF-JK1 VL CDR-Residues 24-34 RASQSIGNYLN L1 of SEQ ID NO.: 27 TNF-JK1 VL CDR- Residues50-56 AASSLQS L2 of SEQ ID NO.: 27 TNF-JK1 VL CDR- Residues 89-95QESYSLI L3 of SEQ ID NO.: 27 TNF-Y7C VH 28EVQLVQSGAEVKKPGASVKVSCKTSGYTFS NYDIN WVRQPTGQGLEWMG WMDPNNGNTGY AQKFVGRVTMTRDTSKTTAYLELSGLKSED TAVYYCAR SSGSGGTWYKEYFQS WGQGTMV TVSS TNF-Y7CVH CDR- Residues 31-35 NYDIN H1 of SEQ ID NO.: 28 TNF-Y7C VH CDR-Residues 50-66 WMDPNNGNTGYAQKFVG H2 of SEQ ID NO.: 28 TNF-Y7C VH CDR-Residues 99-112 KSSGSGGTWYKEYFQS H3 of SEQ ID NO.: 28 TNF-Y7C VL 29DIVMTQSPLSLPVTPGEPASISC RSSQSLL HSNGYNYLD WYLQKPGQFPQLLIY LGSYRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYC MQRIEFPPGT FGQGTKLGIK TNF-Y7C VL CDR-Residues 24-39 RSSQSLLHSNGYNYLD L1 of SEQ ID NO.: 29 TNF-Y7C VL CDR-Residues 55-61 LGSYRAS L2 of SEQ ID NO.: 29 TNF-Y7C VL CDR- Residues94-103 MQRIEFPPGT L3 of SEQ ID NO.: 29 AE11-7 VH 30EVQLVQSGAEVKKPGASVKVSCKTSGYSLT QYPIH WVRQAPGQRPEWMG WISPGNGNTKL SPKFQGRVTLSRDASAGTVFMDLSGLTSDD TAVYFCTS VDLGDH WGQGTLVTVSS AE11-7 VH CDR-Residues 31-35 QYPIH H1 of SEQ ID NO.: 30 AE11-7 VH CDR- Residues 50-66WISPGNGNTKLSPKFQG H2 of SEQ ID NO.: 30 AE11-7 VH CDR- Residues 99-104VDLGDH H3 of SEQ ID NO.: 30 AE11-7 VL 31 DIVMTQSPEFQSVTPKEKVTITC RASQSIGSSLH WYQQKPDQSPKLLIN YASQSFS GVPS RFSGGGSGTDFTLTINSLEAEDAATYYC HQSSNLPIT FGQGTRLEIK AE11-7 VL CDR- Residues 24-34 RASQSIGSSLH L1 of SEQID NO.: 31 AE11-7 VL CDR- Residues 50-56 YASQSFS L2 of SEQ ID NO.: 31AE11-7 VL CDR- Residues 89-97 HQSSNLPIT L3 of SEQ ID NO.: 31 AE11-13 VH32 EVQLVESGGGLVQPGRSLRLSCAASGFTFD DYPMH WVRQAPGEGLEWVS GISSNSASIGYADSVKG RFTISRDNAQNTLYLQMNSLGDED TAVYYCVS LTLG IGQGTLVTVSS AE11-13 VHCDR- Residues 31-35 DYPMH H1 of SEQ ID NO.: 32 AE11-13 VH CDR- Residues50-66 GISSNSASIGYADSVKG H2 of SEQ ID NO.: 32 AE11-13 VH CDR- Residues99-102 LTLG H3 of SEQ ID NO.: 32 AE11-13 VL 33 DIRLTQSPSSLSASVGDRVTITCRASQSIG NYLH WYQQKPGKAPKLLIY AASSLQS GVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYSTLYS FGQGTKLEIK AE11-13 VL CDR- Residues 24-34 RASQSIGNYLH L1 ofSEQ ID NO.: 33 AE11-13 VL CDR- Residues 50-56 AASSLQS L2 of SEQ ID NO.:33 AE11-13 VL CDR- Residues 89-97 QQSYSTLYS L3 of SEQ ID NO.: 33

1.2: Affinity Maturation of the Fully Human Anti-Human TNF AntibodyAE11-5

The AE11-5 human antibody to human TNF was affinity matured by in vitrodisplay technology. One light chain library was constructed to containlimited mutagenesis at the following residues: 28, 31, 32, 51, 55, 91,92, 93, 95a and 96 (Kabat numbering). This library also containedframework germline back-mutations D1E, M4L, H11Q, R49K, H76N and Q103Kas well as toggled residues at position 50(R/K) and 94(S/L) to allow forframework germlining during library selections. Two heavy chainlibraries were made to contain limited mutagenesis in CDRH1 and CDRH2 atresidues 30, 31, 33, 50, 52, and 55 to 58 (Kabat numbering) or in CDRH3at residues 95 to 100b. The library containing CDRH1 and CDRH2diversities also had framework germline back-mutations A18V and L64Q andtoggled residue at 54(L/F) and 78(V/A). The CDRH3 library has anadditional toggled residue at 100c(A/F).

All three libraries were selected separately for the ability to bindhuman or cynomolgus monkey TNF in the presence of decreasingconcentrations of biotinylated human or cynomolgus monkey TNF antigens.All mutated CDR sequences recovered from library selections wererecombined into additional libraries and the recombined libraries weresubjected to more stringent selection conditions before individualantibodies are identified.

Table 11 provides a list of amino acid sequences of VH regions ofaffinity matured fully human TNF antibodies derived from AE11-5 Aminoacid residues of individual CDRs of each VH sequence are indicated inbold.

TABLE 11 List of amino acid sequences of affinity matured AE11-5 VHvariants SEQ ID Clone NO: VH J685M2S2- 94EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 10VH ISWVRQAPGQGLEWMGGITPILGSANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 95EVQLVQSGAEVKKPGSSVKVSCKASGGTFSYYS 12VH ISWVRQAPGQGLEWMGGIMPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 96EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 13VH ISWVRQAPGQGLEWMGGIIPILGSPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 97EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 14VH ISWVRQAPGQGLEWMGGIIPILGSPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 98EVQLVQSGAEVKKPGSSVKVSCKASGGTFAWYS 16VH ISWVRQAPGQGLEWMGGITPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 99EVQLVQSGAEVKKPGSSVKVSCKASGGTFSFYA 18VH ISWVRQAPGQGLEWMGGITPILGAATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 100EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYA 1VH ISWVRQAPGQGLEWMGGITPILGAAVYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 101EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 21VH ISWVRQAPGQGLEWMGGIMPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 102EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 23VH ISWVRQAPGQGLEWMGGITPILGVAVYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 103EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 25VH ISWVRQAPGQGLEWMGGITPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 104EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 27VH ISWVRQAPGQGLEWMGGITPILGSAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 105EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 28VH ISWVRQAPGQGLEWMGGITPILGSAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 106EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 29VH ISWVRQAPGQGLEWMGGITPILGTAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 107EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYT 31VH ISWVRQAPGQGLEWMGGIIPILRNPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 108EVQLVQSGAEVKKPGSSVKVSCKASGGTFSYYA 32VH ISWVRQAPGQGLEWMGGIMPILGTPTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 109EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYT 35VH ISWVRQAPGQGLEWMGGIIPILGAPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 110EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 37VH ISWVRQAPGQGLEWMGGITPILGSATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 111EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYS 38VH ISWVRQAPGQGLEWMGGIMPILGSASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 112EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 43VH ISWVRQAPGQGLEWMGGIMPILGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 113EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYS 44VH ISWVRQAPGQGLEWMGGITPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 114EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 45VH ISWVRQAPGQGLEWMGGIMPILGTATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 115EVQLVQSGAEVKKPGSSVKVSCKASGGTFSFYT 46VH ISWVRQAPGQGLEWMGGIMPILGSPHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 116EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 47VH ISWVRQAPGQGLEWMGGITPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 117EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 48VH ISWVRQAPGQGLEWMGGIMPILGSATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 118EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 4VH ISWVRQAPGQGLEWMGGIIPILGTPTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 119EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 50VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J685M2S2- 120EVQLVQSGAEVKKPGSSVKVSCKASGGTFSLYT 51VH ISWVRQAPGQGLEWMGGIMPILGAPRYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 121EVQLVQSGAEVKKPGSSVKVSCKASGGTFSYYA 52VH ISWVRQAPGQGLEWMGGIMPILGSPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 122EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYA 53VH ISWVRQAPGQGLEWMGGILPILGSPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 123EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYA 55VH ISWVRQAPGQGLEWMGGIIPILGSPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 124EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 56VH ISWVRQAPGQGLEWMGGIVPILGAPLYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 125EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYA 58VH ISWVRQAPGQGLEWMGGIMPILGAPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 126EVQLVQSGAEVKKPGSSVKVSCKASGGTFSYYT 5VH ISWVRQAPGQGLEWMGGIMPILGTPAYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 127EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYS 61VH ISWVRQAPGQGLEWMGGITPILGAATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 128EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 62VH ISWVRQAPGQGLEWMGGIIPILGTPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 129EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 63VH ISWVRQAPGQGLEWMGGIIPILGTPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 130EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 64VH ISWVRQAPGQGLEWMGGITPILGIGNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 131EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYA 66VH ISWVRQAPGQGLEWMGGIVPILGAATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 132EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 67VH ISWVRQAPGQGLEWMGGITPILGSSTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 133EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 68VH ISWVRQAPGQGLEWMGGIMPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 134EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 6VH ISWVRQAPGQGLEWMGGITPILGNSIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 135EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 70VH ISWVRQAPGQGLEWMGGITPILGSPIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 136EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 71VH ISWVRQAPGQGLEWMGGIMPILGTPTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 137EVQLVQSGAEVKKPGSSVKVSCKASGGTFSYYA 72VH ISWVRQAPGQGLEWMGGITPILGAANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 138EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 73VH ISWVRQAPGQGLEWMGGITPILGAAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 139EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 75VH ISWVRQAPGQGLEWMGGITPILGTATYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 140EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYS 76VH ISWVRQAPGQGLEWMGGITPILGSAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 141EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 77VH ISWVRQAPGQGLEWMGGITPILGNAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 142EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 78VH ISWVRQAPGQGLEWMGGITPILRSAVYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 143EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYS 7VH ISWVRQAPGQGLEWMGGIMPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 144EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 80VH ISWVRQAPGQGLEWMGGITPILGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 145EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 81VH ISWVRQAPGQGLEWMGGITPILGTAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 146EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 82VH ISWVRQAPGQGLEWMGGITPILGSPAYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 147EVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYA 83VH ISWVRQAPGQGLEWMGGIIPILGPASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 148EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 84VH ISWVRQAPGQGLEWMGGITPILDAAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 149EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 86VH ISWVRQAPGQGLEWMGGIMPILGIPNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 150EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYA 87VH ISWVRQAPGQGLEWMGGITPILGSAIYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 151EVQLVQSGAEVKKPGSSVKVSCKASGGTFSYYA 88VH ISWVRQAPGQGLEWMGGIMPILGTATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 152EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 89VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFDPKRADYWGQGTLVTVSS J685M2S2- 153EVQLVQSGAEVKKPGSSVKVSCKASGGTFNWYT 8VH ISWVRQAPGQGLEWMGGIMPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 154EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 90VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFDFTRADYWGQGTLVTVSS J685M2S2- 155EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 91VH ISWVRQAPGQGLEWMGGIIPILRFPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 156EVQLVQSGAEVKKPGSSVKVSCKVSGGTFSWYS 92VH ISWVRQAPGQGLEWMGGILPILDTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 157EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 93VH ISWVRQAPGQGLEWMGGIMPILGTAVYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J685M2S2- 158EVQLVQSGAEVKKPGSSVKVSCKASGGTFSIYS 94VH ISWVRQAPGQGLEWMGGILPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J688M2-11VH 159EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPTRADYWGQGTLVTVSS J688M2-13VH 160EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPSRADYWGQGTLVTVSS J688M2-14VH 161EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFNPTRADYWGQGTLVTVSS J688M2-16VH 162EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPARFDYWGQGTLVTVSS J688M2-20VH 163EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYNPSRADYWGQGTLVTVSS J688M2-21VH 164EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPKRADYWGQGTLVTVSS J688M2-22VH 165EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPRRADYWGQGTLVTVSS J688M2-28VH 166EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG FYYDPTRADYWGQGTLVTVSS J688M2-29VH 167EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDFTRADYWGQGTLVTVSS J688M2-2VH 168EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYFDPKRADYWGQGTLVTVSS J688M2-37VH 169EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFDPTRADYWGQGTLVTVSS J688M2-3VH 170EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPSRADYWGQGTLVTVSS J688M2-46VH 171EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARS LYYERTRADYWGQGTLVTVSS J688M2-48VH 172EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARW RFYIPIRFDYWGQGTLVTVSS J688M2-4VH 173EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDFTRADYWGQGTLVTVSS J688M2-50VH 174EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LFYDPSRADYWGQGTLVTVSS J688M2-52VH 175EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPVRADYWGQGTLVTVSS J688M2-56VH 176EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPIRADYWGQGTLVTVSS J688M2-57VH 177EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J688M2-58VH 178EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYNPIRFDYWGQGTLVTVSS J688M2-64VH 179EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFDPARADYWGQGTLVTVSS J688M2-65VH 180EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VFFDPTRADYWGQGTLVTVSS J688M2-68VH 181EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VFYNPTRADYWGQGTLVTVSS J688M2-69VH 182EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYEGPSADYWGQGTLVTVSS J688M2-6VH 183EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYAPNRADYWGQGTLVTVSS J688M2-73VH 184EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LFYDPTRADYWGQGTLVTVSS J688M2-74VH 185EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYNPTRADYWGQGTLVTVSS J688M2-75VH 186EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPARADYWGQGTLVTVSS J688M2-7VH 187EVQLVQSGAEVKKSGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPGRADYWGQGTLVTVSS J688M2-81VH 188EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFDPSRADYWGQGTLVTVSS J688M2-82VH 189EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYFDPSRFDYWGQGTLVTVSS J688M2-83VH 190EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYFDFTRADYWGQGTLVTVSS J688M2-84VH 191EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPTRADYWGQGTLVTVSS J688M2-88VH 192EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYFDPSRADYWGQGTLVTVSS J688M2-89VH 193EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPSRFDYWGQGTLVTVSS J688M2-8VH 194EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG QYYDTSRADYWGQGTLVTVSS J688M2-90VH 195EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARS LYYDTTRFDYWGQGTLVTVSS J688M2-92VH 196EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VFYDPTRADYWGQGTLVTVSS J688M2-94VH 197EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPARADYWGQGTLVTVSS J688M2-95VH 198EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LFYDPRRADYWGQGTLVTVSS J688M2-96VH 199EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDTTRADYWGQGTLVTVSS J693FRM2S- 200EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 2L-32VHISWVRQAPGQGLEWMGGIIPILGTANYAQKFQG RVTITADESTSTVYMELSSLRSEDTAVYYCARGLYYDPARADYWGQGTLVTVSS J693FRM2S- 201 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA2L-40VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCSRG LYYDPTRADYWGQGTLVTVSS J693FRM2S- 202EVQLVQSGAEVMKPGSSVKVSCKASGGTFSSYA 2L-70VHISWVRQAPGQGLEWMGGIIPILGTANYAQKFQG RVTITADESTSTVYMELSSLRSEDTAVYYCTRGLYYDPTRADYWGQGTLVTVSS J693FRM2-S 203 EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYA2R-29VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693FRM2S- 204EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 2R-46VHISWVRQAPGQGLEWMGGIIPILGTANYAQKFQG RVTITADESTSTVYMELSSLRSEDTAVYYCTRGLYYDPTRADYWGQGTLVTVSS J693FRM2S- 205 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA2R-65VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCTRG IYYDPTRADYWGQGTLVTVSS J693M2S2L- 206EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 17VH ISWVRQAPGQGLEWMGGIIPILGTANYAQEFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2L- 207EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 32VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCVRG LYYDPTRADYWGQGTLVTVSS J693M2S2L- 208EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 67VH ISWVRQAPGQGLEWMGGIIPILGTASYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2L- 209EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 75VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCAKG LYYDPTRADYWGQGTLVTVSS J693M2S2L- 210EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 78VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCERG LYYDPTRADYWGQGTLVTVSS J693M2S2L- 211EVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYA 79VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2L- 212EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 94VH ISWVRQAPGQGLEWMGGIIPILGTANYAHKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2R- 213EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 22VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADCWGQGTLVTVSS J693M2S2R- 214EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 24VH ISWVQQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2R- 215EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 2VH ISWVRQAPGQGLEWMGGITPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2R- 216EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 31VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2R- 217EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 71VH TSWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2R- 218EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA 84VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFLGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J693M2S2R- 219EVQLVQSGAEVKKPGSSVKVSCKASGGTSSSYA 89VH ISWVRQAPGQGLEWMGGIIPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPTRADYWGQGTLVTVSS J703M1S3- 220EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 10VH ISWVRQAPGQGLEWMGGITPILGSATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPKRADYWGQGTLVTVSS J703M1S3- 221EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 11VH ISWVRQAPGQGLEWMGGITPILGAASYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPTRADYWGQGTLVTVSS J703M1S3- 222EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 12VH ISWVRQAPGQGLEWMGGITPILGAASYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPARADYWGQGTLVTVSS J703M1S3- 223EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 13VH ISWVRQAPGQGLEWMGGITPILGAANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 224EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 14VH ISWVRQAPGQGLEWMGGIMPILGSPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPRRADYWGQGTLVTVSS J703M1S3- 225EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 16VH ISWVRQAPGQGLEWMGGITPILGSATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 226EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 17VH ISWVRQAPGQGLEWMGGIVPILGTPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 227EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 18VH ISWVRQAPGQGLEWMGGITPILGSANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPARADYWGQGTLVTVSS J703M1S3- 228EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 19VH ISWVRQAPGQGLEWMGGITPILGSPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 229EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 1VH ISWVRQAPGQGLEWMGGIMPILGTPVYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDFRRANYWGQGTLVTVSS J703M1S3- 230EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 20VH ISWVRQAPGQGLEWMGGITPILGAATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 231EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 21VH ISWVRQAPGQGLEWMGGITPILGDPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 232EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 22VH ISWVRQAPGQGLEWMGGITPILGNPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDYKRADYWGQGTLVTVSS J703M1S3- 233EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 25VH ISWVRQAPGQGLEWMGGITPILGSANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LFYDFRRADYWGQGTLVTVSS J703M1S3- 234EVQLVQSGAEVKKPGSSVKVSCKASGGTFAWYA 28VH ISWVRQAPGQGLEWMGGITPILGNAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 235EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 29VH ISWVRQAPGQGLEWMGGITPILGNPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 236EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 2VH TSWVRQAPGQGLEWMGGITPILGSPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDHRRADYWGQGTLVTVSS J703M1S3- 237EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 34VH ISWVRQAPGQGLEWMGGITPILGSPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDYKRADYWGQGTLVTVSS J703M1S3- 238EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 37VH ISWVRQAPGQGLEWMGGITPILGSAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 239EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 38VH ISWVRQAPGQGLEWMGGITPILGTPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDFKRADYWGQGTLVTVSS J703M1S3- 240EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 3VH ISWVRQAPGQGLEWMGGIMPILGTPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPRRADYWGQGTLVTVSS J703M1S3- 241EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 41VH ISWVRQAPGQGLEWMGGITPILGSANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 242EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 42VH ISWVRQAPGQGLEWMGGITPILGAPVYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 243EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 45VH ISWVRQAPGQGLEWMGGITPILGSAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 244EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 46VH ISWVRQAPGQGLEWMGGITPILGSPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 245EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 47VH ISWVRQAPGQGLEWMGGIMPILGSANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 246EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 4VH ISWVRQAPGQGLEWMGGITPILGNAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 247EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 50VH ISWVRQAPGQGLEWMGGITPILGAATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 248EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 51VH ISWVRQAPGQGLEWMGGITPILGSPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDYRRADYWGQGTLVTVSS J703M1S3- 249EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 53VH ISWVRQAPGQGLEWMGGIMPILGIPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPARADYWGQGTLVTVSS J703M1S3- 250EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 54VH ISWVRQAPGQGLEWMGGITPILGSPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 251EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 57VH ISWVRQAPGQGLEWMGGITPILGSAVYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 252EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 5VH ISWVRQAPGQGLEWMGGITPILGSAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDYKRADYWGQGTLVTVSS J703M1S3- 253EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 62VH ISWVRQAPGQGLEWMGGITPILGYPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 254EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 6VH ISWVRQAPGQGLEWMGGITPILGAATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDFRRADYWGQGTLVTVSS J703M1S3- 255EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYP 72VH ISWVRQAPGQGLEWMGGITPILGSAIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDFRRADYWGQGTLVTVSS J703M1S3- 256EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 78VH ISWVRQAPGQGLEWMGGITPILGTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 257EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 79VH ISWVRQAPGQGLEWMGGITPILGSAVYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 258EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 7VH ISWVRQAPGQGLEWMGGITPILGNPIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPARADYWGQGTLVTVSS J703M1S3- 259EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 81VH ISWVRQAPGQGLEWMGGIMPILGAPNYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDYTRADYWGQGTLVTVSS J703M1S3- 260EVQLVQSGAEVKKPGSSVKVSCKASGGTFAWYA 83VH ISWVRQAPGQGLEWMGGITPILGSPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 261EVQLVQSGAEVKKPGSSVKVSCKASGGTFGWYA 86VH TSWVRQAPGQGLEWMGGIIPILGTPNYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 262EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 87VH ISWVRQAPGQGLEWMGGIMPILGTPTYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDPKRADYWGQGTLVTVSS J703M1S3- 263EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYT 88VH ISWVRQAPGQGLEWMGGIMPILGSPNYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG IYYDPKRADYWGQGTLVTVSS J703M1S3- 264EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 91VH ISWVRQAPGQGLEWMGGIMPILGSATYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYFDPKRADYWGQGTLVTVSS J703M1S3- 265EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYA 93VH ISWVRQAPGQGLEWMGGITPILGAANYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG LYYDPKRADYWGQGTLVTVSS J703M1S3- 266EVQLVQSGAEVKKPGSSVKVSCKASGGTFSWYP 9VH ISWVRQAPGQGLEWMGGITPILGAGIYAQKFQGRVTITADESTSTVYMELSSLRSEDTAVYYCARG VYYDFKRADYWGQGTLVTVSS

Table 12 provides a list of amino acid sequences of VL regions ofaffinity matured fully human TNF antibodies derived from AE11-5 Aminoacid residues of individual CDRs of each VH sequence are indicated inbold.

TABLE 12 List of amino acid sequences of affinity matured AE11-5 VLvariants SEQ ID Clone NO: VL J685M2S2-17Vk 267EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPPTF GQGTKVEIK J685M2S2-94Vk 268EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPPTF GQWTKVEIK J688M2-37Vk 269EIVLTQSPDFQSVTPKEKVTITCRARQSIGSSL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTNFTLTINSLEAEDAATYYCHQSSSSPPPTF GQGTKVEIK J688M2-90Vk 270EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPPTF GQGTKVEIK J693FRM2S2L- 271EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 26Vk HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNRSSPPSTF GQGTKVEIK J693FRM2S2L- 272EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 27Vk HWYQQKPDQSPKLLIKYASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPVTF GQGTKVEIK J693FRM2S2L- 273EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 29Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSNLPAPTF GQGTKVEIK J693FRM2S2L- 274EIVLTQSPDFQSVTPKEKVTITCRASQIIGGSL 39Vk HWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQPICSPPRTF GQGTKVEIK J693FRM2S2L- 275EIVLTQSPDFQSVTPKEKVTITCRASQTIGSNL 3Vk HWYQQKPDQSPKLLIKYASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSISPPATF GQGTKVEIK J693FRM2S2L- 276EIVLTQSPDFQSVTPKEKVTITCRASQCIGTSL 40Vk HWYQQKPDQSPKLLIKYDSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSSPPPTF GQGTKVEIK J693FRM2S2L- 277EIVLTQSPDFQSVTPKEKVTITCRASQNIGNSL 42Vk HWYQQKPDQSPKLLIKYTSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTSSLPLPTF GQGTKVEIK J693FRM2S2L- 278EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 43Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQISDLPTSTF GQGTKVEIK J693FRM2S2L- 279EIVLTQSPDFQSVTPKEKVTITCRASQRIGSNL 45Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSSLPPPTF GQGTKVEIK J693FRM2S2L- 280EIVLTQSPDFQSVTPKEKVTITCRASQCIGSSL 46Vk HWYQQKPDQSPKLLIKHTSQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSNSSPLSTF GQGTKVEIK J693FRM2S2L- 281EIVLTQSPDFQSVTPKEKVTITCRASQNIGGSL 47Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSLPLPTF GQGTKVEIK J693FRM2S2L- 282EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 48Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSKSPPPTF GQGTKVEIK J693FRM2S2L- 283EIVLTQSPDFQSVTPKEKVTITCRASQSIGSCL 52Vk HWYQQKPDQSPKLLIKYASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSLPTPTF GQGTKVEIK J693FRM2S2L- 284EIVLTQSPDFQSVTPKEKVTITCRASQSIGGRL 53Vk HWYQQKPDQSPKLLIKYASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQASSSPSTTF GQGTKVEIK J693FRM2S2L- 285EIVLTQSPDFQSVTPKEKVTITCRASQRIGPSL 54Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSCLPSTTF GQGTKVEIK J693FRM2S2L- 286EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 58Vk HWYQQKPDQSPKLLIKYASQSRSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGISPPTTF GQGTKVEIK J693FRM2S2L- 287EIVLTQSPDFQSVTPKEKVTITCRASQSIGTSL 59Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGMSSPAPTF GQGTKVEIK J693FRM2S2L- 288EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 5Vk HWYQQKPDQSPKLLIKYASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRRNSPPPTF GQGTKVEIK J693FRM2S2L- 289EIVLTQSPDFQSVTPKEKVTITCRASQKIGSGL 88Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNNSSPHKTF GQGTKVEIK J693FRM2S2L- 290EIVLTQSPDFQSVTPKEKVTITCRASQTIGSNL 89Vk HWYQQKPDQSPKLLIKHSSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSSPLPTF GQGTKVEIK J693FRM2S2L- 291EIVLTQSPDFQSVTPKEKVTITCRASQNIGRSL 8Vk HWYQQKPDQSPKLLIKYASQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRSSPPPTF GQGTKVEIK J693FRM2S2L- 292EIVLTQSPDFQSVTPKEKVTITCRASQCIGKSL 90Vk HWYQQKPDQSPKLLIKHPSQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSIGLPPTTF GQGTKVEIK J693FRM2S2L- 293EIVLTQSPDFQSVTPKEKVTITCRASQTIGSSL 91Vk HWYQQKPDQSPKLLIKHASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSISPPATF GQGTKVEIK J693FRM2S2L- 294EIVLTQSPDFQSVTPKEKVTITCRASQSIGSTL 92Vk HWYQQKPDQSPKLLIKYESQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRCCSPTQTF GQGTKVEIK J693FRM2S2L- 295EIVLTQSPDFQSVTPKEKVTITCRASQSIGRKL 94Vk HWYQQKPDQSPKLLIKYSSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRSPPTTF GQGTKVEIK J693FRM2S2R- 296EIVLTQSPDFQSVTPKEKVTITCRASQTIGTSL 10Vk HWYQQKPDQSPKLLIKHASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPSPTF GQGTKVEIK J693FRM2S2R- 297EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 11Vk HWYQQKPDQSPKLLIKHVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRGSSPPRTF GQGTKVEIK J693FRM2S2R- 298EIVLTQSPDFQSVTPKEKVTITCRASQTIGSTL 12Vk HWYQQKPDQSPKLLIKHTSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSSPPPTF GQGTKVEIK J693FRM2S2R- 299EIVLTQSPDFQSVTPKEKVTITCRASQSIGSNL 14Vk HWYQQKPDQSPKLLIKHGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRHSSPRATF GQGTKVEIK J693FRM2S2R- 300EIVLTQSPDFQSVTPKEKVTITCRASQKIGSNL 15Vk HWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSSPPATF GQGTKVEIK J693FRM2S2R- 301EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 16Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRSPFRTF GQGTKVEIK J693FRM2S2R- 302EIVLTQSPDFQSVTPKEKVTITCRASQCIGRRL 34Vk HWYQQKPDQSPKLLIKHASQSRSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCTSSPPPTF GQGTKVEIK J693FRM2S2R- 303EIVLTQSPDFQSVTPKEKVTITCRASQRIGSNL 36Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSLRLPPQTF GQGTKVEIK J693FRM2S2R- 304EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 39Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNRSLPRLTF GQGTKVEIK J693FRM2S2R- 305EIVLTQSPDFQSVTPKEKVTITCRASQSIGSCL 3Vk HWYQQKPDQSPKLLIKYASQSISGVPSSSVASGSGTDFTLTINSLEAEDAATYYCHQRSSLPQPTF GQGTKVEIK J693FRM2S2R- 306EIVLTQSPDFQSVTPKEKVTITCRASQSIGRRL 42Vk HWYQQKPDQSPKLLIKHPSQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSIDSPPPTF GQGTKVEIK J693FRM2S2R- 307EIVLTQSPDFQSVTPKEKVTITCRASQTIGRSL 45Vk HWYQQKPDQSPKLLIKYKSQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRWGLPMPTF GQGTKVEIK J693FRM2S2R- 308EIVLTQSPDFQSVTPKEKVTITCRASQRIGSML 48Vk HWYQQKPDQSPKLLIKHSSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTNSLPPRTF GQGTKVEIK J693FRM2S2R- 309EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 50Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSRSPLDTF GQGTKVEIK J693FRM2S2R- 310EIVLTQSPDFQSVTPKEKVTITCRASQSIGCSL 51Vk HWYQQKPDQSPKLLIKYASQSVSVVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSTLPPPTF GQGTKVEIK J693FRM2S2R- 311EIVLTQSPDFQSVTPKEKVTITCRASQGIGTSL 52Vk HWYQQKPDQSPKLLIKHDSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTSSLPPPTF GQGTKVEIK J693FRM2S2R- 312EIVLTQSPDFQSVTPKEKVTITCRASQIIGSSL 56Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPLPTF GQGTKVEIK J693FRM2S2R- 313EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 58Vk HWYQQKPDQSPKLLIKYTSQSKSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGNRSPSTTF GQGTKVEIK J693FRM2S2R- 314EIVLTQSPDFQSVTPKEKVTITCRASKRIGSSL 59Vk HWYQQKPDQSPKLLIKHKSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSASPPPTF GQGTKVEIK J693FRM2S2R- 315EIVLTQSPDFQSVTPKEKVTITCRASQTIGSSL 5Vk HWYQQKPDQSPKLLIKHPSQSMSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSTSPPATF GQGTKVEIK J693FRM2S2R- 316EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 60Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSLPTPTF GQGTKVEIK J693FRM2S2R- 317EIVLTQSPDFQSVTPKEKVTITCRASQSIGSTL 61Vk HWYQQKPDQSPKLLIKHASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSNCSPAHTF GQGTKVEIK J693FRM2S2R- 318EIVLTQSPDFQSVTPKEKVTITCRASQTIGSRL 62Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSRLPPPTF GQGTKVEIK J693FRM2S2R- 319EIVLTQSPDFQSVTPKEKVTITCRASQRIGSTL 63Vk HWYQQKPDQSPKLLIKHASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSCSPQATF GQGTKVEIK J693FRM2S2R- 320EIVLTQSPDFQSVTPKEKVTITCRASQSIGTSL 64Vk HWYQQKPDQSPKLLIKYPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGRSPPHTF GQGTKVEIK J693FRM2S2R- 321EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 65Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSILPPPTF GQGTKVEIK J693FRM2S2R- 322EIVLTQSPDFQSVTPKEKVTITCRASQCIGSYL 92Vk HWYQQKPDQSPKLLIKHVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPTLTF GQGTKVEIK J693FRM2S2R- 323EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 93Vk HWYQQKPDQSPKLLIKHASQSMSGVPSGFSGSGSGTDFTLTINSLEAEDAATYYCHQTNRSPPPTF GQGTKVEIK J693FRM2S2R- 324EIVLTQSPDFQSVTPKEKVTITCRASQNIGTSL 9Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLNINSLEAEDAATYYCHQSSCLPRPTF GQGTKVEIK J693M2S2L- 325EIVLTQSPDFQSVTPKEKVTITCRASQSIGSPL 10Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSSSPPPTF GQGTKVEIK J693M2S2L- 326EIVLTQSPDFQSVTPKEKVTITCRASQSIGSTL 11Vk HWYQQKPDQSPKLLIKHDSQSKSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSDSPAPTF GQGTKVEIK J693M2S2L- 327EIVLTQSPDFQSVTPKEKVTITCRASQSIGSCL 12Vk HWYQQKPDQSPKLLIKHASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRISPLPTF GQGTKVEIK J693M2S2L- 328EIVLTQSPDFQSVTPKEKVTITCRASQSIGRRL 13Vk HWYQQKPDQSPKLLIKHSSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSSLPHPTF GQGTKVEIK J693M2S2L- 329EIVLTQSPDFQSVTPKEKVTITCRASQRIGSRL 14Vk HWYQQKPDQSPKLLIKHASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSCSSPLVTF GQGTKVEIK J693M2S2L- 330EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 16Vk HWYQQKPDQSPKLLIKHASQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGSSPQATF GQGTKVEIK J693M2S2L- 331EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 17Vk HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNRGSPPQTF GQGTKVEIK J693M2S2L- 332EIVLTQSPDFQSVTPKEKVTITCRASQTIGSIL 18Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNTSLPPPTF GQGTKVEIK J693M2S2L- 333EIVLTQSPDFQSVTPKEKVTITCRASQSIGNSL 19Vk HWYQQKPDQSPKLLIKYPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSRLPVPTF GQGTKVEIK J693M2S2L-1Vk 334EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL HWYQQKPDQSPKLLIKHTSQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPAPTF GQGTKVEIK J693M2S2L- 335EIVLTQSPDFQSVTPKEKVTITCRASQNIGSSL 20Vk HWYQQKPDQSPKLLIKHVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSNSLPAPTF GQGTKVEIK J693M2S2L- 336EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 21Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSMSLPSATF GQGTKVEIK J693M2S2L- 337EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 22Vk HWYQQKPDQSPKLLIKHLSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQPCRLPPSTF GQGTKVEIK J693M2S2L- 338EIVLTQSPDFQSVTPKEKVTITCRASQSIGSLL 23Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSCSSPRHTF GQGTKVEIK J693M2S2L- 339EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 24Vk HWYQQKPDQSPKLLIKHPSQSKSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRSPAPTF GQGTKVEIK J693M2S2L- 340EIVLTQSPDFQSVTPKEKVTITCRASQSIGGSL 25Vk HWYQQKPDQSPKLLIKYSSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSILPSLTF GQGTKVEIK J693M2S2L- 341EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 26Vk HWYQQKPDQSPKLLIKHPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRNLPPRTF GQGTKVEIK J693M2S2L- 342EIVLTQSPDFQSVTPKEKVTITCRASQSIGSIL 27Vk HWYQQKPDQSPKLLIKYGSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNGSSPPRTF GQGTKVEIK J693M2S2L- 343EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 28Vk HWYQQKPDQSPKLLIKYFSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSCLPMQTF GQGTKVEIK J693M2S2L- 344EIVLTQSPDFQSVTPKEKVTITCRASQNIGSSL 29Vk HWYQQKPDQSPKLLIKYSSQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSISPPATF GQGTKVEIK J693M2S2L-2Vk 345EIVLTQSPDFQSVTPKEKVTITCRASQCIGSSL HWYQQKPDQSPKLLIKHASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSTCLPPRTF GQGTKVEIK J693M2S2L- 346EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 30Vk HWYQQKPDQSPKLLIKYVSQSMSGVLSRFSGSGSGTDFTLTINSLEAEDAATYYCHQPSTSPRPTF GQGTKVEIK J693M2S2L- 347EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 31Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSLPPSTF GQGTKVEIK J693M2S2L- 348EIVLTQSPDFQSVTPKEKVTITCRASQSIGCSL 32Vk HWYQQKPDQSPKLLIKYASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPSSTF GQGTKVEIK J693M2S2L- 349EIVLTQSPDFQSVTPKEKVTITCRASQIIGTSL 33Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRSPPRTF GQGTKVEIK J693M2S2L- 350EIVLTQSPDFQSVTPKEKVTITCRASQKIGTSL 34Vk HWYQQKPDQSPKLLIKHESQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSGSPPPTF GQGTKVEIK J693M2S2L- 351EIVLTQSPDFQSVTPKEKVTITCRASQTIGGSL 35Vk HWYQQKPDQSPKLLIKHVSQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSISPPPTF GQGTKVEIK J693M2S2L- 352EIVLTQSPDFQSVTPKEKVTITCRASQSIGSDL 36Vk HWYQQKPDQSPKLLIKHVSQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSCMSPSLTF GQGTKVEIK J693M2S2L- 353EIVLTQSPDFQSVTPKEKVTITCRASQSIGSNL 37Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPNTTF GQGTKVEIK J693M2S2L- 354EIVLTQSPDFQSVTPKEKVTITCRASQRIGSIL 38Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGRISPSSTF GQGTKVEIK J693M2S2L- 355EIVLTQSPDFQSVTPKEKVTITCRASQSIGNRL 39Vk HWYQQKPDQSPKLLIKHASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGSLPTLTF GQGTKVEIK J693M2S2L-3Vk 356EIVLTQSPDFQSVTPKEKVTITCRASQTIGSSL HWYQQKPDQSPKLLIKHDSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSLPTHTF GQGTKVEIK J693M2S2L- 357EIVLTQSPDFQSVTPKEKVTITCRASQTIGRSL 40Vk HWYQQKPDQSPKLLIKHGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRSSPPSTF GQGTKVEIK J693M2S2L- 358EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 41Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNCSSPPPTF GQGTKVEIK J693M2S2L- 359EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 44Vk HWYQQKPDQSPKLLIKYESQSDSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRRNSPPSTF GQGTKVEIK J693M2S2L- 360EIVLTQSPDFQSVTPKEKVTITCRASQGIGSRL 45Vk HWYQQKPDQSPKLLIKHGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNRGLPAPTF GQGTKVEIK J693M2S2L- 361EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 46Vk HWYQQKPDQSPKLLIKYASQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNHTSPPPTF GQGTKVEIK J693M2S2L- 362EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 47Vk HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGRLPPPTF GQGTKVEIK J693M2S2L-4Vk 363EIVLTQSPDFQSVTPKEKVTITCRASQYIGKRL HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSNISPPPTF GQGTKVEIK J693M2S2L- 364EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 51Vk HWYQQKPDQSPKLLIKHESQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPPPTF GQGTKVEIK J693M2S2L- 365EIVLTQSPDFQSVTPKEKVTITCRASQTIGSSL 52Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSLPPSTF GQGTKVEIK J693M2S2L- 366EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 54Vk HWYQQKPDQSPKLLIKHPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSSSPAQTF GQGTKVEIK J693M2S2L- 367EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 55Vk HWYQQKPDQSPKLLIKHTSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSLPLPTF GQGTKVEIK J693M2S2L- 368EIVLTQSPDFQSVTPKEKVTITCRASQWIGSSL 56Vk HWYQQKPDQSPKLLIKHTSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPPQTF GQGTKVEIK J693M2S2L- 369EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 58Vk HWYQQKPDQSPKLLIKYSSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSSSPPPTF GQGTKVEIK J693M2S2L- 370EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 59Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRLPPSTF GQGTKVEIK J693M2S2L-5Vk 371EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKYGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNWSLPLPTF GQGTKVEIK J693M2S2L- 372EIVLTQSPDFQSVTPKEKVTITCRASQRIGTSL 62Vk HWYQQKPDQSPKLLIKYASQSKSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSCSPTPTF GQGTKVEIK J693M2S2L- 373EIVLTQSPDFQSVTPKEKVTITCRASQSIGGSL 64Vk HWYQQKPDQSPKLLIKYGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRCVSPSPTF GQGTKVEIK J693M2S2L- 374EIVLTQSPDFQSVTPKEKVTITCRASQSIGGTL 65Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPARTF GQGTKVEIK J693M2S2L- 375EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 66Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCGSSPLHTF GQGTKVEIK J693M2S2L- 376EIVLTQSPDFQSVTPKEKVTITCRASQSIGTSL 67Vk HWYQQKPDQSPKLLIKHPSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSTSSPPPTF GQGTKVEIK J693M2S2L- 377EIVLTQSPDFQSVTPKEKVTITCRASQNIGSSL 68Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSGLPLPTF GQGTKVEIK J693M2S2L- 378EIVLTQSPDFQSVTPKEKVTITCRASQSIGRRL 69Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSSSPSPTF GQGTKVEIK J693M2S2L-6Vk 379EIVLTQSPDFQSVTPKEKVTITCRASQRIGGNL HWYQQKPDQSPKLLIKHESQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPSHTF GQGTKVEIK J693M2S2L- 380EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 70Vk HWYQQKPDQSPKLLIKYASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSSSPSHTF GQGTKVEIK J693M2S2L- 381EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 71Vk HWYQQKPDQSPKLLIKHASQSMSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRNSPPTTF GQGTKVEIK J693M2S2L- 382EIVLTQSPDFQSVTPKEKVTITCRASQRIGSRL 72Vk HWYQQKPDQSPKLLIKHGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSSPPPTF GQGTKVEIK J693M2S2L- 383EIVLTQSPDFQSVTPKEKVTITCRASQNIGSSL 74Vk HWYQQKPDQSPKLLIKYASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSLLPAPTF GQGTKVEIK J693M2S2L- 384EIVLTQSPDFQSVTPKEKVTITCRASQIIGTTL 75Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSNLPPSTF GQGTKVEIK J693M2S2L- 385EIVLTQSPDFQSVTPKEKVTITCRASQNIGGNL 76Vk HWYQQKPDQSPKLLIKHASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSNLPPPTF GQGTKVEIK J693M2S2L- 386EIVLTQSPDFQSVTPKEKVTITCRASQGIGGSL 77Vk HWYQQKPDQSPKLLIKYASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSACLPTRTF GQGTKVEIK J693M2S2L- 387EIVLTQSPDFQSVTPKEKVTITCRASQSIGTSL 78Vk HWYQQKPDQSPKLLIKYASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQIGSLPPPTF GQGTKVEIK J693M2S2R- 388EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 13Vk HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSRLPPPTF GQGTKVEIK J693M2S2R- 389EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 14Vk HWYQQKPDQSPKLLIKHNSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSSPPLTF GQGTKVEIK J693M2S2R- 390EIVLTQSPDFQSVTPKEKVTITCRASQSIGRNL 15Vk HWYQQKPDQSPKLLIKHVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSRSPPSTF GQGTKVEIK J693M2S2R- 391EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 16Vk HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSSLPAPTF GQGTKVEIK J693M2S2R- 392EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 17Vk HWYQQKPDQSPKLLIKHASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRLPPQTF GQGTKVEIK J693M2S2R- 393EIVLTQSPDFQSVTPKEKVTITCRASQCIGSRL 18Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRGRLPPRTF GQGTKVEIK J693M2S2R- 394EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 19Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSTSLPRLTF GQGTKVEIK J693M2S2R- 395EIVLTQSPDFQSVTPKEKVTITCRASQIIGSSL 20Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRSSPQQTF GQGTKVEIK J693M2S2R- 396EIVLTQSPDFQSVTPKEKVTITCRASQSIGSTL 21Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPPPTF GQGTKVEIK J693M2S2R- 397EIVLTQSPDFQSVTPKEKVTITCRASQSIGNSL 22Vk HWYQQKPDQSPKLLIKHGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRRSSPRHTF GQGTKVEIK J693M2S2R- 398EIVLTQSPDFQSVTPKEKVTITCRASQRIGRRL 27Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSIGSPPLTF GQGTKVEIK J693M2S2R- 399EIVLTQSPDFQSVTPKEKVTITCRASQSIGRGL 29Vk HWYQQKPDQSPKLLIKYGSQSMSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPPPTF GQGTKVEIK J693M2S2R-2Vk 400EIVLTQSPDFQSVTPKEKVTITCRASQSIGCSL HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCTSLPLPTF GQGTKVEIK J693M2S2R- 401EIVLTQSPDFQSVTPKEKVTITCRASQGIGSSL 30Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSSLPTPTF GQGTKVEIK J693M2S2R- 402EIVLTQSPDFQSVTPKEKVTITCRASQSIGTSL 31Vk HWYQQKPDQSPKLLIKHASQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSRLPPLTF GQGTKVEIK J693M2S2R- 403EIVLTQSPDFQSVTPKEKVTITCRASQVIGGVL 32Vk HWYQQKPDQSPKLLIKYTSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPRPTF GQGTKVEIK J693M2S2R- 404EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 33Vk HWYQQKPDQSPKLLIKHSSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSNSPHRTF GQGTKVEIK J693M2S2R- 405EIVLTQSPDFQSVTPKEKVTITCRASQSIGRTL 36Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSISPQPTF GQGTKVEIK J693M2S2R- 406EIVLTQSPDFQSVTPKEKVTITCRASQRIGNTL 37Vk HWYQQKPDQSPKLLIKYPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGSSPPPTF GQGTKVEIK J693M2S2R- 407EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 39Vk HWYQQKPDQSPKLLIKYISQSMSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSCGLPPPTF GQGTKVEIK J693M2S2R-3Vk 408EIVLTQSPDFQSVTPKEKVTITCRASQNIGTRL HWYQQKPDQSPKLLIKYGSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRISPPPTF GQGTKVEIK J693M2S2R- 409EIVLTQSPDFQSVTPKEKVTITCRASQSIGSTL 40Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSRLPPPTF GQGTKVEIK J693M2S2R- 410EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 44Vk HWYQQKPDQSPKLLIKYASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSNLPSPTF GQGTKVEIK J693M2S2R- 411EIVLTQSPDFQSVTPKEKVTITCRASQSIGSNL 45Vk HWYQQKPDQSPKLLIKHASQSMSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPRPTF GQGTKVEIK J693M2S2R- 412EIVLTQSPDFQSVTPKEKVTITCRASQIIGSSL 46Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSISSPSPTF GQGTKVEIK J693M2S2R- 413EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 47Vk HWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSNCLPPPTF GQGTKVEIK J693M2S2R- 414EIVLTQSPDFQSVTPKEKVTITCRASQSIGKSL 48Vk HWYQQKPDQSPKLLIKHESQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQANSLPPPTF GQGTKVEIK J693M2S2R-4Vk 415EIVLTQSPDFQSVTPKEKVTITCRASQSIGRRL HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSSSPPSTF GQGTKVEIK J693M2S2R- 416EIVLTQSPDFQSVTPKEKVTITCRASQIIGHSL 52Vk HWYQQKPDQSPKLLIKHASQSILGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSIKSPPATF GQGTKVEIK J693M2S2R- 417EIVLTQSPDFQSVTPKEKVTITCRASQSIGTSL 54Vk HWYQQKPDQSPKLLIKHTSQSKSGVPSRFSGSGSGTDFALTINSLEAEDAATYYCHQSSNSPRYTF GQGTKVEIK J693M2S2R- 418EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 55Vk HWYQQKPDQSPKLLIKHASQSHSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGGSPPWTF GQGTKVEIK J693M2S2R- 419EIVLTQSPDFQSVTPKEKVTITCRASQGIGRSL 56Vk HWYQQKPDQSPKLLIKYASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSNRSPPPTF GQGTKVEIK J693M2S2R-5Vk 420EIVLTQSPDFQSVTPKEKVTITCRASQSIGTTL HWYQQKPDQSPKLLIKHVSQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPHPTF GQGTKVEIK J693M2S2R- 421EIVLTQSPDFQSVTPKEKVTITCRASQIIGSSL 60Vk HWYQQKPDQSPKLLIKYPSQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSWSSPLMTF GQGTKVEIK J693M2S2R- 422EIVLTQSPDFQSVTPKEKVTITCRASQSIGNTL 61Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPPTF GQGTKVEIK J693M2S2R- 423EIVLTQSPDFQSVTPKEKVTITCRASQRIGICL 62Vk HWYQQKPDQSPKLLIKYASQSMSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGFSLPPATF GQGTKVEIK J693M2S2R- 424EIVLTQSPDFQSVTPKEKVTITCRASQSIGSCL 63Vk HWYQQKPDQSPKLLIKYPSQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSCSPTTTF GQGTKVEIK J693M2S2R- 425EIVLTQSPDFQSVTPKEKVTITCRASQRIGNTL 64Vk HWYQQKPDQSPKLLIKYPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGSSPPPTF GQGTKVEIK J693M2S2R- 426EIVLTQSPDFQSVTPKEKVTITCRASQTIGTSL 65Vk HWYQQKPDQSPKLLIKYASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRCSLPPPTF GQGTKVEIK J693M2S2R- 427EIVLTQSPDFQSVTPKEKVTITCRASQSIGGSL 68Vk HWYQQKPDQSPKLLIKYASQSHSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCRISPRPTF GQGTKVEIK J693M2S2R- 428EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 69Vk HWYQQKPDQSPKLLIKHPSQSKSGVPSRFSGSGSGTDFTLSINSLEAEDAATYYCHQTSRSPLHTF GQGTKVEIK J693M2S2R-6Vk 429EIVLTQSPDFQSVTPKEKVTITCRASQNIGKNL HWYQQKPDQSPKLLIKYPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRSSPLSTF GQGTKVEIK J693M2S2R- 430EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 70Vk HWYQQKPDQSPKLLIKYMSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRVLPPPTF GQGTKVEIK J693M2S2R- 431EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 71Vk HWYQQKPDQSPKLLIKYGSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSISPRRTF GQGTKVEIK J693M2S2R- 432EIVLTQSPDFQSVTPKEKVTITCRASQTIGRSL 72Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRKSSPTPTF GQGTKVEIK J693M2S2R- 433EIVLTQSPDFQSVTPKEKVTITCRASQRIGRQL 75Vk HWYQQKPDQSPKLLIKHPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPPQTF GQGTKVEIK J693M2S2R- 434EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 77Vk HWYQQKPDQSPKLLIKHTSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQICRSPSPTF GQGTKVEIK J693M2S2R- 435EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 78Vk HWYQQKPDQSPKLLIKYASQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSGSPAPTF GQGTKVEIK J693M2S2R- 436EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 79Vk HWYQQKPDQSPKLLIKYSSQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQISSSPPPTF GQGTKVEIK J693M2S2R-7Vk 437EIVLTQSPDFQSVTPKEKVTITCRASQTIGNSL HWYQQKPDQSPKLLIKHASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTMTSPPPTF GQGTKVEIK J693M2S2R- 438EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 80Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRSSPSPTF GQGTKVEIK J693M2S2R- 439EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 81Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRRWSPPPTF GQGTKVEIK J693M2S2R- 440EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 82Vk HWYQQKPDQSPKLLIKYASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQISCLPLPTF GQGTKVEIK J693M2S2R- 441EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 83Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSISLPPPTF GQGTKVEIK J693M2S2R- 442EIVLTQSPDFQSVTPKEKVTITCRASQSIGRNL 84Vk HWYQQKPDQSPKLLIKHTSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTSTLPPQTF GQGTKVEIK J693M2S2R- 443EIVLTQSPDFQSVTPKEKVTITCRASQSIGRSL 85Vk HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRNSPQPTF GQGTKVEIK J693M2S2R- 444EIVLTQSPDFQSVTPKEKVTITCRASQSIGTRL 86Vk HWYQQKPDQSPKLLIKYVSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSHSPPPTF GQGTKVEIK J693M2S2R- 445EIVLTQSPDFQSVTPKEKVTITCRASQSIGSCL 87Vk HWYQQKPDQSPKLLIKHRSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQWSSSPPPTF GQGTKVEIK J693M2S2R- 446EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL 89Vk HWYQQKPDQSPKLLIKHPSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTSGSPSHTF GQGTKVEIK J693M2S2R-8Vk 447EIVLTQSPDFQSVTPKEKVTITCRASQGIGSSL HWYQQKPDQSPKLLIKYESQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPPTF GQGTKVEIK J693M2S2R- 448EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL 90Vk HWYQQKPDQSPKLLIKHDSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSSSPPTTF GQGTKVEIK J693M2S2R- 449EIVLTQSPDFQSVTPKEKVTITCRASQTIGSNL 91Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRISSPPSTF GQGTKVEIK J693M2S2R- 450EIVLTQSPDFQSVTPKEKVTITCRASQTIGSSL 92Vk HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSCSSPPSTF GQGTKVEIK J693M2S2R- 451EIVLTQSPDFQSVTPKEKVTITCRASQTIGSSL 93Vk HWYQQKPDQSPKLLIKYVSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTISSPLPTF GQGTKVEIK J693M2S2R- 452EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL 95Vk HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSCSPAHTF GQGTKVEIK J703M1S3-11Vk 453EIVLTQSPDFQSVTPKEKVTITCRDSRCIGSNL HWYQQKPDQSPKLLIKHASQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCSSSPPPTF GQGTKVEIK J703M1S3-13Vk 454EIVLTQSPDFQSVTPKEKVTITCRASQSIGSTL HWYQQKPDQSPKLLIKHASQSNSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPPPTF GQGTKVEIK J703M1S3-16Vk 455EIVLTQSPDFQSVTPKEKVTITCRASQSIGDSL HWYQQKPDQSPKLLIKHASQSKSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGSTSPPRTF GQGTKVEIK J703M1S3-19Vk 456EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHGSQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSWSSPIPTF GQGTKVEIK J703M1S3-22Vk 457EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL HWYQQKPDQSPKLLIKYASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSNLPSPTF GQGTKVEIK J703M1S3-26Vk 458EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL HWYQQKPDQSPKLLIKHASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSGSSPPRTF GQGTKVEIK J703M1S3-29Vk 459EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRTSSPVRTF GQGTKVEIK J703M1S3-2Vk 460EIVLTQSPDFQSVTPKEKVTITCRASQSIGNTL HWYQQKPDQSPKLLIKHVSQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQKVSSPSPTF GQGTKVEIK J703M1S3-30Vk 461EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL HWYQQKPDQSPKLLIKHASQSVSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSRSSPPPTF GQGTKVEIK J703M1S3-33Vk 462EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPPSTF GQGTKVEIK J703M1S3-34Vk 463EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSSPSTTF GQGTKVEIK J703M1S3-57Vk 464EIVLTQSPDFQSVTPKEKVTITCRASQCIGSSL HWYQQKPDQSPKLLIKHESQSSSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRCTSPSPTF GQGTKVEIK J703M1S3-5Vk 465EIVLTQSPDFQSVTPKEKVTITCRASQRIGSSL HWYQQKPDQSPKLLIKHPSQSDSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNCSLPLPTF GQGTKVEIK J703M1S3-62Vk 466EIVLTQSPDFQSVTPKEKVTITCRASQCIGSSL HWYQQKPDQSPKLLIKHASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQGISSPPQTF GQGTKVEIK J703M1S3-69Vk 467EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHVSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSSPSPTF GQGTKVEIK J703M1S3-71Vk 468EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHPSQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSIRLPPSTF GQGTKVEIK J703M1S3-78Vk 469EIVLTQSPDFQSVTPKEKVTITCRANQSIGGSL HWYQQKPDQSPKLLIKHASQSKSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQDSRSPTRTF GQGTKVEIK J703M1S3-79Vk 470EIVLTQSPDFQSVTPKEKVTITCRASQSIGSGL HWYQQKPDQSPKLLIKHTSQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSLPHPTF GQGTKVEIK J703M1S3-7Vk 471EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSSSPTPTF GQGTKVEIK J703M1S3-81Vk 472EIVLTQSPDFQSVTPKEKVTITCRASQSIGSRL HWYQQKPDQSPKLLIKYPSQSRSGVPSRFSGSGSGTDLTLTINSLEAEDAATYYCHQNGSLPPPTF GQGTKVEIK J703M1S3-82Vk 473EIVLTQSPDFQSVTPKEKVTITCRASQSIGSSL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSSPPPTF GQGTKVEIK J703M1S3-86Vk 474EIVLTQSPDFQSVTPKEKVTITCRASQSIGSAL HWYQQKPDQSPKLLIKHASQSLSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQSSILPRPTF GQGTKVEIK J703M1S3-90Vk 475EIVLTQSPDFQSVTPKEKVTITCRASQSIGSNL HWYQQKPDQSPKLLIKHASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQTRTSPPLTF GQGTKVEIK J703M1S3-93Vk 476EIVLTQSPDFQSVTPKEKVTITCRASQKIGSSL HWYQQKPDQSPKLLIKYGSQSTSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQCISLPTPTF GQGTKVEIK J703M1S3-94Vk 477EIVLTQSPDFQSVTPKEKVAITCRASQRIGSSL HWYQQKPDQSPKLLIKYASQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQNSSLPPPTF GQGTKVEIK

TABLE 13 Amino acid residues observed in affinity matured AE11-5antibodies AE11-5 Heavy chain variable region (SEQ ID NO: 1073) AE11-5VH1234567890123456789012345678901234567890123456789012a345678901EVQLVQSGAEVKKPGSSAKVSCKASGGTFS SYAIS WVRQAPGQGLEWMG GIIPILGTANYAQ                 V           NW TTT              WT   FRSPI                             TY SV                M   TDAST                             GI P                 L   I NGS                             AN G                 V     P V                              F                   N     I H                              R                         V A                              L                         K R                                                        F M                                                          L234567890123456789012abc345678901234567890abc1234567890123 KFLGRVTITADESTSTVYMELSSLRSEDTAVYYCAR GLYYDPTRADY WGQGTLVTVSS  Q             A                   SVFFNTSWF                                    WIVVEFASM                                    TFP TRKP                                    ARH IGRA                                     Q  ADI                                          Y                                          V                                          P                                          N                                          G AE11-5 Light chain variableregion (SEQ ID NO: 1074) AE11-5VL1234567890123456789012345678901234567890123456789012345678901DIVMTQSPDFHSVTPKEKVTITC RASQSIGSSLH WYQQKPDQSPKLLIR HASQSIS GVPSRE  L      Q                R  RR                KYV   L                           T  TT                  P   V                           N  GN                  T   T                           I  NC                  G   S                           C  KG                  S   M                           G  CI                  E   N                           K  HK                  D   K                           Y  VM                      F                           W  PL                      R                              LY                                P                               V2345678901234567890123456789012345a67890123456aFSGSGSGTDFTLTIHSLEAEDAATYYC HQSSSSPPPT FGQGTQVEIK              N              RRRL LS      K                             NGI  AR                             GIC  SL                             TCG  RT                             CNN  TA                             ITT  QQ                              MK  HH                                   V                                   M

TABLE 14 Individual VH sequences from converted clones Protein Sequenceregion SEQ ID NO: 123456789012345678901234567890 J703M1S3 478EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #2 WYATSWVRQAPGQGLEWMGGITPILGSPIY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDHRRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYATS #2 of SEQ ID VH NO.: 478 J703M1S3 CDR-H2Residues 50-66 GITPILGSPIYAQKFQG #2 of SEQ ID VH NO.: 478 J703M1S3CDR-H3 Residues 99-109 GVYYDHRRADY #2 of SEQ ID VH NO.: 478 J703M1S3 479EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #13 WYAISWVRQAPGQGLEWMGGITPILGAANY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDPKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #13 of SEQ ID NO.: 479 J703M1S3 CDR-H2Residues 50-66 GITPILGAANYAQKFQG #13 of SEQ ID VH NO.: 479 J703M1S3CDR-H3 Residues 99-109 GVYYDPKRADY #13 of SEQ ID VH NO.: 479 J703M1S3480 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #26 WYAISWVRQAPGQGLEWMGGITPILGTANY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDPKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #26 of SEQ ID VH NO.: 480 J703M1S3 CDR-H2Residues 50-66 GITPILGTANYAQKFQG #26 of SEQ ID VH NO.: 480 J703M1S3CDR-H3 Residues 99-109 GVYYDPKRADY #26 of SEQ ID VH NO.: 480 J703M1S3481 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #30 WYAISWVRQAPGQGLEWMGGITPILGSPIY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDPKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #30 of SEQ ID VH NO.: 481 J703M1S3 CDR-H2Residues 50-66 GITPILGSPIYAQKFQG #30 of SEQ ID VH NO.: 481 J703M1S3CDR-H3 Residues 99-109 GVYYDPKRADY #30 of SEQ ID VH NO.: 481 J703M1S3482 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #33 WYPISWVRQAPGQGLEWMGGITPILGAGIY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDFKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYPIS #33 of SEQ ID VH NO.: 482 J703M1S3 CDR-H2Residues 50-66 GITPILGAGIYAQKFQG #33 of SEQ ID VH NO.: 482 J703M1S3CDR-H3 Residues 99-109 GVYYDFKRADY #33 of SEQ ID VH NO.: 482 J703M1S3483 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #35 WYAISWVRQAPGQGLEWMGGITPILGSATY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGIYYDPKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #35 of SEQ ID VH NO.: 483 J703M1S3 CDR-H2Residues 50-66 GITPILGSATYAQKFQG #35 of SEQ ID VH NO.: 483 J703M1S3CDR-H3 Residues 99-109 GIYYDPKRADY #35 of SEQ ID VH NO.: 483 J703M1S3484 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #38 WYAISWVRQAPGQGLEWMGGITPILGTPIY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDFKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #38 of SEQ ID VH NO.: 484 J703M1S3 CDR-H2Residues 50-66 GITPILGTPIYAQKFQG #38 of SEQ ID VH NO.: 484 J703M1S3CDR-H3 Residues 99-109 GVYYDFKRADY #38 of SEQ ID VH NO.: 484 J703M1S3485 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #69 WYAISWVRQAPGQGLEWMGGITPILGSPIY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGIYYDPKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #69 of SEQ ID VH NO.: 485 J703M1S3 CDR-H2Residues 50-66 GITPILGSPIYAQKFQG #69 of SEQ ID VH NO.: 485 J703M1S3CDR-H3 Residues 99-109 GIYYDPKRADY #69 of SEQ ID VH NO.: 485 J703M1S3486 EVQLVQSGAEVKKPGSSVKVSCKASGGTFS #90 WYAISWVRQAPGQGLEWMGGITPILGSPIY VHAQKFQGRVTITADESTSTVYMELSSLRSED TAVYYCARGVYYDYKRADYWGQGTLVTVSS J703M1S3CDR-H1 Residues 31-35 WYAIS #90 of SEQ ID VH NO.: 486 J703M1S3 CDR-H2Residues 50-66 GITPILGSPIYAQKFQG #90 of SEQ ID VH NO.: 486 J703M1S3CDR-H3 Residues 99-109 GVYYDYKRADY #90 of SEQ ID VH NO.: 486

TABLE 15 Individual clones VL sequences Protein Sequence region123456789012345678901234567890 J703M1S3 487EIVLTQSPDFQSVTPKEKVTITCRASQSIG #2 NTLHWYQQKPDQSPKLLIKHVSQSVSGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ KVSSPSPTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQSIGNTLH #2 of SEQ ID VL NO.: 487 J703M1S3 CDR-L2Residues 50-56 HVSQSVS #2 of SEQ ID VL NO.: 487 J703M1S3 CDR-L3 Residues89-98 HQKVSSPSPT #2 of SEQ VL ID NO.: 487 J703M1S3 488EIVLTQSPDFQSVTPKEKVTITCRASQSIG #13 STLHWYQQKPDQSPKLLIKHASQSNSGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ SSSLPPPTFGQGTKVEI J703M1S3 CDR-L1Residues 24-34 RASQSIGSTLH #13 of SEQ ID VL NO.: 488 J703M1S3 CDR-L2Residues 50-56 HASQSNS #13 of SEQ ID VL NO.: 488 J703M1S3 CDR-L3Residues 89-98 HQSSSLPPPT #13 of SEQ VL ID NO.: 488 J703M1S3 489EIVLTQSPDFQSVTPKEKVTITCRASQSIG #26 SRLHWYQQKPDQSPKLLIKHASQSTSGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ SGSSPPRTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQSIGSRLH #26 of SEQ ID VL NO.: 489 J703M1S3 CDR-L2Residues 50-56 HASQSTS #26 of SEQ ID VL NO.: 489 J703M1S3 CDR-L3Residues 89-98 HQSGSSPPRT #26 of SEQ VL ID NO.: 489 J703M1S3 490EIVLTQSPDFQSVTPKEKVTITCRASQRIG #30 SSLHWYQQKPDQSPKLLIKHASQSVSGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ SRSSPPPTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQRIGSSLH #30 of SEQ ID VL NO.: 490 J703M1S3 CDR-L2Residues 50-56 HASQSVS #30 of SEQ ID VL NO.: 490 J703M1S3 CDR-L3Residues 89-98 HQSRSSPPPT #30 of SEQ VL ID NO.: 490 J703M1S3 491EIVLTQSPDFQSVTPKEKVTITCRASQSIG #33 SSLHWYQQKPDQSPKLLIKHASQSTSGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ SSSSPPSTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQSIGSSLH #33 of SEQ ID VL NO.: 491 J703M1S3 CDR-L2Residues 50-56 HASQSTS #33 of SEQ ID VL NO.: 491 J703M1S3 CDR-L3Residues 89-98 HQSSSSPPST #33 of SEQ VL ID NO.: 491 J703M1S3 492EIVLTQSPDFQSVTPKEKVTITCRASQTIG #35 SSLHWYQQKPDQSPKLLIKHASQSISGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ TSSLPTPTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQTIGSSLH #35 of SEQ ID VL NO.: 492 J703M1S3 CDR-L2Residues 50-56 HASQSIS #35 of SEQ ID VL NO.: 492 J703M1S3 CDR-L3Residues 89-98 HQTSSLPTPT #35 of SEQ VL ID NO.: 492 J703M1S3 493EIVLTQSPDFQSVTPKEKVTITCRASQTIG #38 SSLHWYQQKPDQSPKLLIKHASQSISGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ SSSSPPPTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQTIGSSLH #38 of SEQ ID VL NO.: 493 J703M1S3 CDR-L2Residues 50-56 HASQSIS #38 of SEQ ID VL NO.: 493 J703M1S3 CDR-L3Residues 89-98 HQSSSSPPPT #38 of SEQ VL ID NO.: 493 J703M1S3 494EIVLTQSPDFQSVTPKEKVTITCRASQSIG #69 SSLHWYQQKPDQSPKLLIKHVSQSLSGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ RSSSPSPTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQSIGSSLH #69 of SEQ ID VL NO.: 494 J703M1S3 CDR-L2Residues 50-56 HVSQSLS #69 of SEQ ID VL NO.: 494 J703M1S3 CDR-L3Residues 89-98 HQRSSSPSPT #69 of SEQ VL ID NO.: 494 J703M1S3 495EIVLTQSPDFQSVTPKEKVTITCRASQSIG #90 SNLHWYQQKPDQSPKLLIKHASQSISGVPS VLRFSGSGSGTDFTLTINSLEAEDAATYYCHQ TRTSPPLTFGQGTKVEIK J703M1S3 CDR-L1Residues 24-34 RASQSIGSNLH #90 of SEQ ID VL NO.: 495 J703M1S3 CDR-L2Residues 50-56 HASQSIS #90 of SEQ ID VL NO.: 495 J703M1S3 CDR-L3Residues 89-98 HQTRTSPPLT #90 of SEQ VL ID NO.: 495

TABLE 16 AE11-5 affinity matured scFv clones converted to full lengthIgG Full length ScFv IgG (protein) clone name HC plasmid LC plasmid nameJ703M1S3#2 pJP368; pHybE-hCg1,z,non- pJP369; pHybE-hCk V3- AE11-5 AM1a,mut(234,235)-J703M1S3#2 J703M1S31#2 J703M1S3#13 pJP370;pHybE-hCg1,z,non- pJP371; pHybE-hCk V3- AE11-5 AM2a,mut(234,235)-J703M1S3#13 J703M1S3#13 J703M1S3#26 pJP372;pHybE-hCg1,z,non- pJP373; pHybE-hCk V3- AE11-5 AM3a,mut(234,235)-J703M1S3#26 J703M1S3#26 J703M1S3#30 pJP374;pHybE-hCg1,z,non- pJP375; pHybE-hCk V3- AE11-5 AM4a,mut(234,235)-J703M1S3#30 J703M1S3#30 J703M1S3#33 pJP376;pHybE-hCg1,z,non- pJP377; pHybE-hCk V3- AE11-5 AM5a,mut(234,235)-J703M1S3#33 J703M1S3#33 J703M1S3#35 pJP378;pHybE-hCg1,z,non- pJP379; pHybE-hCk V3- AE11-5 AM6a,mut(234,235)-J703M1S3#35 J703M1S3#35 J703M1S3#38 pJP382;pHybE-hCg1,z,non- pJP383; pHybE-hCk V3- AE11-5 AM8a,mut(234,235)-J703M1S3#38 J703M1S3#38 J703M1S3#69 pJP384;pHybE-hCg1,z,non- pJP385; pHybE-hCk V3- AE11-5 AM9a,mut(234,235)-J703M1S3#69 J703M1S3#69 J703M1S3#90 pJP386;pHybE-hCg1,z,non- pJP387; pHybE-hCk V3- AE11-5 AM10a,mut(234,235)-J703M1S3#90 J703M1S3#90

1.3 TNF Enzyme-Linked Immunosorbent Assay Protocol (ELISA) and AssayResult

The following protocol is used to characterize the binding of TNFantibodies to biotinylated human or cyno TNF by enzyme-linkedimmunosorbent assay (ELISA). An ELISA plate was coated with 50 μl perwell of goat anti human IgG-Fc at 2 μg/ml, overnight at 4° C. The platewas washed 3 times with PBS/Tween. 50 μl Mab diluted to 1 μg/ml inPBS/0.1% BSA was added to appropriate wells and incubated for 1 hour atroom temperature (RT). The plate was washed 3 times with PBS/Tween. 50μl of serial diluted biotin-human TNF was added to appropriate wells andincubated for 1 hour at RT. The plate was washed 3 times with PBS/Tween.50 μl of streptavidin-HRP diluted 1:10,000 in PBS/0.1% BSA was added toappropriate wells and incubated for 1 hour at RT. The plate was washed 3times with PBS/Tween. 50 μl of TMB was added to appropriate wells andthe reaction was allowed to proceed for 1 minute. The reaction wasstopped with 50 μl/well 2N H₂SO₄ and the absorbance read at 450 nm.Results are shown in Table 17.

TABLE 17 EC50 in hTNF EC50 in cynoTNF IgG Name ELISA (nM) ELISA (nM)AE11-5-AM1 1.06 2.14 AE11-5-AM2 522.5 >845 AE11-5-AM3 1.57 1.55AE11-5-AM4 18.32 750.3 AE11-5-AM5 17.7 2.2 AE11-5-AM6 1.37 >720AE11-5-AM7 10.32 1.26 AE11-5-AM8 250.2 58.58 AE11-5-AM9 16.72 5.29AE11-5-AM10 0.98 0.28

1.4 TNF Neutralization Potency of TNF Antibodies by L929 Bioassay

Human TNF was prepared at Abbott Bioresearch Center (Worcester, Mass.,US) and received from the Biologics Pharmacy. Mouse TNF was prepared atAbbott Bioresearch Center and received from the Biologics Pharmacy. RatTNF was prepared at Abbott Bioresearch Center and received from theBiologics Pharmacy. Rabbit TNF was purchased from R&D Systems.Rhesus/Macaque TNF (rhTNF) was purchased from R&D Systems. Actinomycinwas purchased from Sigma Aldrich and resuspended at a stockconcentration of 10 mg/mL in DMSO.

Assay Media: 10% FBS (Hyclone#SH30070.03), Gibco reagents: RPMI 1640(#21870), 2 mM L-glutamine (#25030), 50 units/mL penicillin/50 μg/mLstreptomycin (#15140), 0.1 mM MEM non-essential amino acids (#11140) and5.5×10⁻⁵ M 2-mercaptoethanol (#21985-023).

L929 cells were grown to a semi-confluent density and harvested using0.05% tryspin (Gibco#25300). The cells were washed with PBS, counted,and resuspended at 1E6 cells/mL in assay media containing 4 μg/mLactinomycin D. The cells were seeded in a 96-well plate (Costar#3599) ata volume of 50 μL and 5E4 cells/well. Wells received 50 μL of assaymedia, bringing the volume to 100 μL.

A test sample was prepared as follows. The test and control IgG proteinswere diluted to a 4× concentration in assay media and serial 1:3dilutions were performed. TNF species were diluted to the followingconcentrations in assay media: 400 pg/mL huTNF, 200 pg/mL muTNF, 600pg/mL ratTNF, and 100 pg/mL rabTNF. Antibody sample (200 μL) was addedto the TNF (200 μL) in a 1:2 dilution scheme and allowed to incubate for0.5 hour at room temperature.

To measure huTNF neutralization potency in this assay, the antibody/TNFsolution was added to the plated cells at 100 μL for a finalconcentration at 375 nM-0.019 nM. The final concentration of TNF was asfollows: 100 pg/mL huTNF, 50 pg/mL muTNF, 150 pg/mL ratTNF, and 25 pg/mLrabTNF. The plates were incubated for 20 hours at 37° C., 5% CO₂. Toquantitate viability, 100 μL was removed from the wells and 10 μL ofWST-1 reagent (Roche cat#11644807001) was added. Plates were incubatedunder assay conditions for 3.5 hours, centrifuged at 500×g, and 75 μL ofsupernatant transferred to an ELISA plate (Costar cat#3369). The plateswere read at OD 420-600 nm on a Spectromax 190 ELISA plate reader. Theneutralization potency of selected TNF/IL-17 DVD-Ig binding proteins isshown in Table 18.

TABLE 18 hu TNF neutralization rhesus TNF neutralization IC50 IgG NameIC50 (nM) (nM) AE11-5 AM1 0.439 0.251 AE11-5 AM2 1.241 0.756 AE11-5 AM30.291 0.165 AE11-5 AM4 0.259 0.109 AE11-5 AM5 0.968 0.613 AE11-5 AM62.029 0.652 AE11-5 AM7 0.049 0.104 AE11-5 AM8 1.356 3.040 AE11-5 AM90.391 0.123 AE11-5 AM10 0.678 0.140

Example 2 Affinity Maturation of a Humanized Anti-Human TNF AntibodyhMAK-195

The mouse anti-human TNF antibody MAK-195 was humanized andaffinity-matured to generate a panel of humanized MAK195 variants thathave cross-reactivity to cyno-TNF and improved affinity and bindingkinetics against both human and cyno TNF.

To improve the affinity of hMAK195 to TNF, hypermutated CDR residueswere identified from other human antibody sequences in the IgBLASTdatabase that also shared high identity to germlines VH3-53 andIGKV1-39. The corresponding hMAK195 CDR residues were then subjected tolimited mutagenesis by PCR with primers having low degeneracy at thesepositions to create three antibody libraries in the scFv format. Thefirst library contained mutations at residues 31, 32, 33, 35, 50, 52,53, 54, 56 and 58 in the VH CDR1 and 2 (Kabat numbering); the secondlibrary at residues 95 to 100, 100a, 101, and 102 in VH CDR3; and thethird library at residues 28, 30, 31, 32, 50, 53, 92, 93, 94, and 95 inthe three VL CDRs. To further increase the identity of hMAK195 to thehuman germline framework sequences, a binary degeneracy at VH positions60 (D/A), 61 (S/D), 62 (T/S), 63 (L/V), and 65 (S/G) were introducedinto the first library. Also, a binary degeneracy at VL positions 24(K/R), 33 (V/L), 54 (R/L), 55 (H/Q), 56 (T/S), 91 (H/S) and 96 (F/Y)were introduced into the third library.

These hMAK195 variants were selected against a low concentration ofbiotinylated TNF for improved on-rate, off-rate, or both were carriedout and antibody protein sequences of affinity-modulated hMAK195 wererecovered for converting back to IgG for further characterization. Allthree libraries were selected separately for the ability to bind humanor cynomolgus monkey TNF in the presence of decreasing concentrations ofbiotinylated human or cynomolgus monkey TNF antigens. All mutated CDRsequences recovered from library selections were recombined intoadditional libraries and the recombined libraries were subjected to morestringent selection conditions before individual antibodies areidentified.

Table 19 provides a list of amino acid sequences of VH and VL of thehumanized MAK-195 which were subjected to the affinity maturationselection protocol Amino acid residues of individual CDRs of each VH andVL sequence are indicated in bold.

TABLE 19 List of amino acid sequences of affinity matured hMAK195 VHvariants SEQ ID Clone NO: VH rHC1_B8 496EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRGDGSTDYASTLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_H12 497EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRGDGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E1 498EVQLVESGGGLVQPGGSLRLSCAASGFTFSAYGVNWVRQAPGKGLEWVSIIWGDGATDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_A2 499EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMISSDGFTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_H6 500EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIAADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_D7 501EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGSTDYASSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D9 502EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRDDGSTDYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_A10 503EVQLVESGGGLVQPGGSLRLSCAASGETFSHIGVSWVRQAPGKGLEWVSMISYAGSTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLLHKGPIDYWGQGTLVTVSS H1 + H2_A5 504EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSMIWSDGSTDYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_F8 505EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRADGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D1 506EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVQWVRQAPGKGLEWVSMIRGDGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARPSHHGLIDNWGQGTLVTVSS rHC2_C2 507EVQLVESGGGLVQPGGSLRLSCAASGFTFSELGVNWVRQAPGKGLEWVSYISDVGSTYYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWHHGRFDYWGQGTLVTVSS rHC1_G4 508EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSLIRADGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_F3 509EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGFTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWQHGPSVYWGQGTLVTVSS rHC1_B4 510EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRADGVTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G3 511EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVHWVRQAPGKGLEWVSMIGADGYTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D7 512EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMISADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D5 513EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRSDGFTDYADSVKGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E4 514EVQLVESGGGLVQPGGSLRLSCAASGFTFSEYGVNWVRQAPGKGLEWVSIIWHDGSTAYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_E10 515EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSLIRGDGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B6 516EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVSWVRQAPGKGLEWVSMIWGDGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_B7 517EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRDDGSTYYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLGYWGQGTLVTVSS H1 + H2_G8 518EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSMIWAGGSTAYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_G5 519EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSLIGADGSTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQYGPLAYWGQGTLVTVSS H1 + H2_F1 520EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIEGDGGTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC19 521EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPAAYWGQGTLVTVSS H1 + H2_A10 522EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAXGKGLEWVSMISADGTTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_B9 523EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRGDGTTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLGYWGQGTLVTVSS H1 + H2_F7 524EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYGVGWVRQAPGKGLEWVSMIWGAGSTNYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B1 525EVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGVNWVRQAPGKGLEWVSMIWADGTTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_H9 526EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSVIGGDGYTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_A12 527EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGXGLEWVSMISSDGYTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_G8 528EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWSDGSTHYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_B4 529EVQLVESGGGLVQPGGSLRLSCAASGFTFSQLGVTWVRQAPGKGLEWVSTISDAGSTYYASSVKGRFTIIRINSKNTLYLQMNSLRAEDTAVYYCARDWHHGRFAYWGQGTLVTVSS H1 + H2_G5 530EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRGDGSTYYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_C6 531EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVQWVRQAPGKGLEWVSMIRDDGSTSYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_F5 532EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRGDGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_B4 533EVQLVESGGGLVQPGGSLRLSCAASGFTFSAYGVNWVRQAPGKGLEWVSMISGDGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_F6 534EVQLVESGGGLVQPGGSLRLSCAASGFTFSHFGVTWVRQAPGKGLEWVSNIWASGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_B6 535EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS H1 + H2_A3 536EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVNWVRQAPGKGLEWVSVIWGDGSTAYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D10 537EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRGDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC18 538EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWSDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-18 539EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC2_E6 540EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSLIRGDGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D4 541EVQLVESGGGLVQPGGSLRISCAASGFTFSAFGVSWVRQAPGKGLEWVSMIWGDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_F8 542EVQLVESGGGLVQPGGSLRLSCAASGFTFSDLGVNWVRQAPGKGLEWVSTISDIGSTYYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWHNGRFDYWGQGTLVTVSS rHC1_F10 543EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRGDGFTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_C12 544EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_C11 545EVQLVESGGGLVQPGGSLRLSCAASGFTFSHFGVNWVRQAPGKGLEWVSIIWGDGSTAYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_C4 546EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVEWVRQAPGKGLEWVSKIWADGSTDYADSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_E12 547EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSLIWGDGTTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_C4 548EVQLVESGGGLVQPGGSLRLSCAASGFTFSYFGVSWVRQAPGKGLEWVSMIWGDGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_F9 549EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRSDGSTDYADTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_B5 550EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSIIWSDGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS S4-34 551EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_C2 552EVQLVESGGGLVQPGGSLRLSCAASGFTFSEFGVNWVRQAPGKGLEWVSMIWGNGATDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_F11 553EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSMIWGDGTTAYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_E9 554EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B2 555EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSMIWGDGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E9 556EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVNWVRQAXGKGLEWVSMIWGDGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_A6 557EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIGSDGFTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_C8 558EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQTPGKGLEWVSMIRGDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_C5 559EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVSWVRQAPGKGLEWVSQIWGDGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_D5 560EVQLVESGGGLVQPGGSLRLSCAASGFTFSQLGVTWVRQAPGKGLEWVSTISDAGSTYYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWHHGRFAYWGQGTLVTVSS rHC1_C7 561EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWQHGPLGYWGQGTLVTVSS H1 + H2_C3 562EVQLVESGGGLVQPGGSLRLSCAASGFTFSAYGVHWVRQAPGKGLEWVSMIWGDGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_G7 563EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGTTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWQHGPIGYWGQGTLVTVSS rHC1_A5 564EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGYTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_G9 565EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVEWVRQAPGKGLEWVSKIWGDGTTDYADTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E2 566EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIGGEGRTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_C9 567EVQLVESGGGLVQPGGSLRLSCAASGFTFSNLGVNWVRQAPGKGLEWVSMIWDVGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWHHGLFDYWGQGTLVTVSS rHC1_G6 568EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIMGDGYTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_C1 569EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRDDGATDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC1_C2 570EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMISGDGYTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_C1 571EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRGDGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B10 572EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVNWVRQAPGXGLEWVSMIWADGSTDYASTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E3 573EVQLVESGGGLVQPGGSLRLSCAASGFTFSAFGVCWVRQAPGKGLEWVSMIWADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_H4 574EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRSDGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWQHGPEGYWGQGTLVTVSS rHC2_A1 575EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRGDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G11 576EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSLIRSDGSTHYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D8 577EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRGDGYTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_A3 578EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-31 579EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVQWVRQAPGKGLEWVSGIGADGSTAYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHSGLAYWGQGTLVTVSS rHC36 580EVQLVESGGGLVQPGGSLILSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNFKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC2_G3 581EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRGDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_C10 582EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIAADGSTAYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC14 583EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPAAYWGQGTLVTVSS rHC1_D4 584EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGSTDYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_D11 585EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIISGDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_E11 586EVQLVESGGGLVQPGGSLRLSCAASGFTFSDWGVHWMRQAPGKGLEWVSTIWDDGSTYYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGHHGPFVYWGQGTLVTVSS H1 + H2_E7 587EVQLVESGGGLVQPGGSLRLSCAASXFTFSNFGVNWVRQAPGKGLEWVSMIWGDGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_A8 588EVQLVESGGGLVQPGGSLRLSCAASGFTFSVYGVNWVRQAPGKGLEWVSMIGDEGSTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHWHHGAVDYWGQGTLVTVSS H1 + H2_B9 589EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSMIWADGSTHYADSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS S4-19 590EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVEWVRQAPGKGLEWVSGIWADGSTHYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-74 591EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC1_H2 592EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_E3 593EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGYTSYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC34 594EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPSAYWGQGTLVTVSS H1 + H2_F2 595EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRADGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D9 596EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGTTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS H1 + H2_E6 597EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVHWVRQAPGKGLEWVSMIWADGSTVYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_F3 598EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIGSDGSTYYADSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_G11 599EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLGYWGQGTLVTVSS H1 + H2_D3 600EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSMIWGDGHTAYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B12 601EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSMIWAHGATHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B11 602EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSLIRDDGSTDYASTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_A8 603EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWGDGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS S4-24 604EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTHYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_F11 605EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMISADGYTDYADSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_D10 606EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_D6 607EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIGADGYTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G4 608EVQLVESGGGLVQPGGSLRLSCAASGFTFSAFGVSWVRQAPGKGLEWVSMIWADGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D11 609EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSLIRGDGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_E9 610EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC1_A12 611EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVQWVRQAPGKGLEWVSRISGDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_A2 612EVQLVESGGGLVQPGGSLRLSCAASGFSFSNFGVNWVRQAPGKGLEWVSMIWADGSTNYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B7 613EVQLVESGGGLVQPGGSLRLSCAASGFTFSAYGVSWVRQAPGKGLEWVSIISADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_H8 614EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_F12 615EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIGADGYTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_E5 616EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRGDGSTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_A11 617EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSMIWGSGATDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D6 618EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMISADGFTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC2_G10 619EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIAADGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_H3 620EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSLIAADGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_F10 621EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIRGDGSTAYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_C7 622EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIWGDGNTGYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_A9 623EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_E5 624EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSMIWGDGSTEYADTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC62 625EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS H1 + H2_F4 626EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVYWVRQAPGKGLEWVSMIWDDGSTEYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_H8 627EVQLVESGGGLVQPGGSLRLSCAASGFTFSQLGVTWVRQAPGKGLEWVSTISDAGSTYYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDWHHGRFAYWGQGTLVTVSS rHC2_F4 628EVQLVESGGGLVQPGGSLRLSCAASGFTFSGPGVNWVRQAPGKGLEWVSSIWDDGSTYYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHSHDGRFDYWGQGTLVTVSS S4-50 629EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVEWVRQAPGKGLEWVSGIWADGSTHYADTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS H1 + H2_F12 630EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSMIWGEGSTGYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_E6 631EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRDDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_F2 632EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIGGDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS H1 + H2_G6 633EVQLVESGGGLVQPGGSLRLSCAASGFTFSDFGVNWVRQAPGKGLEWVSMIWADGTTDYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC2_F5 634EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSGISADGSTAYDSSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D6 635EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGVSWVRQAPGKGLEWVSLIRGDGSTYYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_A9 636EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVNWVRQAPGKGLEWVSMIWGDGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_A1 637EVQLVESGGGLVQPGGSLRLSCAASGFTFSHFGVNWVRQAPGKGLEWVSMIWADGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC60 638EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPAAYWGQGTLVTVSS rHC1_C8 639EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVHWVRQAPGKGLEWVSMIAGDGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS rHC44 640EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYADTLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_G9 641EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSIIGADGATDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLGYWGQGTLVTVSS H1 + H2_A6 642EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSGITGDGITAYASTLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G2 643EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMISGDGFTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G7 644EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSNIWGDGSTDYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E10 645EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRADGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_E2 646EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_A4 647EVQLVESGGGLVQPGGSLRLSCAASGFTFSAYGVSWVRQAPGKGLEWVSMIWRDGSTDYADSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_H3 648EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVHWVRQAPGKGLEWVSMIWGDGSTHYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_G1 649EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVHWVRQAPGKGLEWVSGISADGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E8 650EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYGVNWVRQAPGKGLEWVSMIGGDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_C9 651EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRADGSTDYASSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_F7 652EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVQWVRQAPGKGLEWVSVISADGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_F6 653EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIGADGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS rHC22 654EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTDYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC2_G5 655EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSLIRGDGYTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_C12 656EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYGVSWVRQAPGKGLEWVSVIRADGVTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS rHC3 657EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIWADGSTHYASSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC1_F1 658EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVQWVRQAPGKGLEWVSRINGDGSTDYASTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_E11 659EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIRSDGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B8 660EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGVNWVRQAPGKGLEWVSMIWVDGSTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G1 661EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVNWVRQAPGKGLEWVSMIWGDGSTYYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_B3 662EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYGVSWVRQAPGKGLEWVSMIRSDGFTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D2 663EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMITGDGYTDYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC1_E12 664EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRADGLTDYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_B5 665EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSLIRSDGSTDYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_D11 666EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGSTDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS H1 + H2_A7 667EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGVIWVRQAPGKGLEWVSMIGGDGSTYYDSSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_G3 668EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVNWVRQAPGKGLEWVSMIGSDGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D5 669EVQLVESGGGLVQPGGSLRLSCAASGFTFSYYGVHWVRQAPGKGLEWVSGISGEGSTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_D1 670EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRGDGSTYYASSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWVKGTLVTVSS rHC1_E7 671EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSIIRGDGSTDYASSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS rHC1_E11 672EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIRADGTTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS S4-55 673EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVTWVRQAPGKGLEWVSMIWADGSTDYASTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS H1 + H2_C10 674EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGVSWVRQAPGKGLEWVSMIRGDGSTYYADTLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS H1 + H2_G10 675EVQLVESGGGLVQPGGSLRLSCAASGFTFSHFGVNWVRQAPGKGLEWVSMIWADGSTSYADSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS

Table 20 provides a list of amino acid sequences of VL regions ofaffinity matured fully human TNF antibodies derived from hMAK195 Aminoacid residues of individual CDRs of each VH sequence are indicated inbold.

TABLE 20 List of amino acid sequences of affinity matured hMAK195 VLvariants SEQ ID Clone NO: VL S3_92 676DIQMTQSPSSLSASVGDRVTITCRASQKVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYHTPYTFGQGTKLEIKS3_79 677 DIQMTQSPSSLSASVGDRVTITCKASQAVSTEVAWYQQKPGKAPKLLIYCASTRQTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQSYSAPYTFGQGTKLEIKS3_68 678 DIQMTQSPSSLSASVGDRVTITCRASQVVSSAVAWYQQKPGKAPKLLIYWASKRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_60 679 DIQMTQSPSSLSASVGDRVTITCRASQAVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS4-63 680 DIQMTQSPSSLSASVGDRVTITCKASQKVSSALAWYQQKPGKAPKLLIYWASALHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRPPFTFGQGTKLEIKS3_5 681 DIQMTQSPSSLSASVGDRVTITCRASQGVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYTTPFTFGQGTKLEIKS3_44 682 DIQMTQSPSSLSASVGDRVTITCRASQGVSRALAWYQQKPGKAPKLLIYWASTLHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRAPFTFGQGTKLEIKS3_53 683 DIQMTQSPSSLSASVGDRVTITCRASQAVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYHTPFTFGQGTKLEIKS3_91 684 DIQMTQSPSSLSASVGDRVTITCKASQGVSSALAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_59 685 DIQMTQSPSSLSASVGDRVTITCKASQGVSSALAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPYTFGQGTKLEIKS3_47 686 DIQMTQSPSSLSASVGDRVTITCKASQWVSSAVAWYQQKPGKAPKLLIYWASTRQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRIPFTFGQGTKLEIKS3_70 687 DIQMTQSPSSLSASVGDRVTITCKASQAVSSALAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPYTFGQGTKLEIKS3_56 688 DIQMTQSPSSLSASVGDRVTITCKASQRVSSAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPYTFGQGTKLEIKS3_37 689 DIQMTQSPSSLSASVGDRVTITCKASQGVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYNTPFTFGQGTKLEIKS3_36 690 DIQMTQSPSSLSASVGDRVTITCKASQKVSSAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_67 691 DIQMTQSPSSLSASVGDRVTITCKASQTVXRAVAWYQQKPGKAPKLLIYWASTRQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQSYSTPFTFGQGTKLEIKS3_40 692 DIQMTQSPSSLSASVGDRVTITCRASQRVSSAVAWSQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYTTPYTFGQGTKLEIKS3_73 693 DIQMTQSPSSLSASVGDRVTITCKASQAVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS4-50 694 DIQMTQSPSSLSASVGDRVTITCKASQLVSSAVAWYQQKPGKAPKLLIYWASALHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSSPYTFGQGTKLEIKS4-6 695 DIQMTQSPSSLSASVGDRVTITCKASQLVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_19 696 DIQMTQSPSSLSASVGDRVTITCKASQKVSSAVAWYQQKPGKAPKLLIYWASARHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRSPFTFGQGTKLEIKS3_83 697 DIQMTQSPSSLSASVGDRVTITCRASQAVSTALAWYQQKPGKAPKLLIYSASTLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRSPFTFGQGTKLEIKS3_78 698 DIQMTQSPSSLSASVGDRVTITCKASQYVGGAVAWYQQKPGKAPKLLIYQASTLQTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHISKPFTFGQGTKLEIKS4-19 699 DIQMTQSPSSLSASVGDRVTITCKASQLVSSAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_58 700 DIQMTQSPSSLSASVGDRVTITCKASQSVNGALAWYQQKPGKAPKLLIYRASTRQTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSIPFTFGQGTKLEIKS4-31 701 DIQMTQSPSSLSASVGDRVTITCRASQGVSSALAWYQQKPGKAPKLLIYWASALHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSAPFTFGQGTKLEIKS3_31 702 DIQMTQSPSSLSASVGDRVTITCKASQAVSSSVAWYQQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYNEPYTFGQGTKLEIKS3_13 703 DIQMTQSPSSLSASVGDRVTITCKASQKVSSAVAWYQQKPGKAPKLLIYWASARHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPYTFGQGTKLEIKS4-40 704 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFSFGQGTKLEIKS3_26 705 DIQMTQSPSSLSASVGDRVTITCRASQAVSSAVAWYQQKPGKAPKLLIYWASKRQTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYISPYTFGQGTKLEIKS3_33 706 DIQMTQSPSSLSASVGDRVTITCKASQGVRSALAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQSYSAPYTFGQGTKLEIKS3_28 707 DIQMTQSPSSLSASVGDRVTITCKASQTVSNAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS4-74 708 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_84 709 DIQMTQSPSSLSASVGDRVTITCKASQPVRSAVAWYQQKPGKAPKLLIYSASTRQTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQSYSIPFTFGQGTKLEIKS4-54 710 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYKTPFSFGQGTKLEIKS3_23 711 DIQMTQSPSSLSASVGDRVTITCRASQAVSSAVAWYQQKPGKAPKLLIYWASSRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_55 712 DIQMTQSPSSLSASVGDRVTITCKASQTVGRAVAWYQQKPGKAPKLLIYWASTRQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQSYSTPFTFGQGTKLEIKS4-34 713 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_76 714 DIQMTQSPSSLSASVGDRVTITCRASQKVSNAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYNSPFTFGQGTKLEIKS4-12 715 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYKTPFTFGQGTKLEIKS3_86 716 DIQMTQSPSSLSASVGDRVTITCRASQRVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYTTPYTFGQGTKLEIKS3_61 717 DIQMTQSPSSLSASVGDRVTITCKASQRVSSAVAWYQQKPGKAPKLLIYWASNRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_18 718 DIQMTQSPSSLSASVGDRVTITCKASQLVSSALAWYQQKPGKAPKLLIYWASTRQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_72 719 DIQMTQSPSSLSASVGDRVTITCKASQLVSSALAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRNPFTFGQGTKLEIKS3_41 720 DIQMTQSPSSLSASVGDRVTITCKASQAVSSALAWYQQKPXKAPKLLIYWASSRQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS4-24 721 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS4-17 722 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_90 723 DIQMTQSPSSLSASVGDRVTITCKASQPVSGAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRASYTFGQGTKLEIKS3_87 724 DIQMTQSPSSLSASVGDRVTITCRASQKVSSAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPYTFGQGTKLEIKS3_66 725 DIQMTQSPSSLSASVGDRVTITCRASQRVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYTTPYTFGQGTKLEIKS4-18 726 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASTLHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_4 727 DIQMTQSPSSLSASVGDRVTITCRASQAVSSAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSSPYTFGQGTKLEIKS3_64 728 DIQMTQSPSSLSASVGDRVTITCKASQPVSSAVAWYQQKPGKAPKLLIYWASTLHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPFTFGQGTKLEIKS3_62 729 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPYTFGQGTNLEIKS3_29 730 DIQMTQSPSSLSASVGDIVTITCKASQLVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRTPYTFGQGTKLEIKS3_65 731 DIQMTQSPSSLSASVGDRVTITCKASQLVSSAVAWYQQKPGKAPKLLIYWASMRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSSPFTFGQGTKLEIKS3_81 732 DIQMTQSPSSLSASVGDRVTITCKASQTVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYRAPYTFGQGTKLEIKS3_39 733 DIQMTQSPSSLSASVGDRVTITCKASQRVSSALAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_49 734 DIQMTQSPSSLSASVGDRVTITCRASQLVSNAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSSPFTFGQGTKLEIKS3_85 735 DIQMTQSPSSLSASVGDRVTITCRASQLVSSAVAWYQQKPGKAPKLLIYWASARHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIKS3_82 736 DIQMTQSPSSLSASVGDRVTITCKASQLVSSAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYTTPFTFGQGTKLEIKS3_93 737 DIQMTQSPSSLSASVGDRVTITCKASQRVSSAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQHYSTPFTFGQGTKLEIK

TABLE 21 Amino acid residues observed in affinity matured hMAK-195.hMAK195 Heavy chain variable region (SEQ ID NO: 1075) hMAK195VHEVQLVESGGGLVQPGGSLRLSCAASGFTFS DYGVN WVRQAPGKGLEWVS MIWGDGSTD                              NFS T              I RAG T A                              HLN S              V GSE F H                              YS  H              L SDA A V                              IR  Q              R AEV Y S                                  Y              K LVG W N                                                 S  NY   GYDSTLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS  ADSVG                                HSQQRTLDS                                       QLRPASGVF                                       LCLLVQDGC                                       YRYNWAETN                                       DFPYEKW P                                       NDARS R I                                       TYVTP P H                                       PPDDI A                                       AICA  I                                       SG C                                       R hMAK195 Light chain variableregion (SEQ ID NO: 1076) hMAK195VL DIQMTQSPSSLSASVGDRVTITC KASQAVSSAVAWYQQKPGKAPKLLIY WASTRHT G                        R   SRRPL                S  SLQS                            VTNT                 R  I T                            GIGG                 L  L A                            DNCV                 C  K E                            TCTS                 Q  A F                            PKIR                 G  R VPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQHYSTPFTFGQGTKLEIK                                  SNRSTY                                  FGPR                                  DTML                                  GIIQ                                  HCAA                                     S

The tables below provide a list of humanized MAK-195 antibodies thatwere converted into IgG proteins for characterization.

TABLE 22 VH sequences of IgG converted clones Protein Sequence regionSEQ ID NO: 123456789012345678901234567890 A8 738EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVNWVRQAPGKGLEWVSMIAADGFTDYASSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWHHGPVAYWGQGTLVTVSS A8 CDR-H1Residues 31-35 NYGVN VH of SEQ ID NO.: 738 A8 CDR-H2 Residues 50-65MIAADGFTDYASSVKG VH of SEQ ID NO.: 738 A8 CDR-H3 Residues 98-106EWHHGPVAY VH of SEQ ID NO.: 738 B5 739 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVSWVRQAPGKGLEWVSLIRGDGSTDYA SSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWHHGPVAYWGQGTLVTVSS B5 CDR-H1 Residues 31-35 NYGVS VH of SEQ IDNO.: 739 B5 CDR-H2 Residues 50-65 LIRGDGSTDYASSLKG VH of SEQ ID NO.: 739B5 CDR-H3 Residues 98-106 EWHHGPVAY VH of SEQ ID NO.: 739 rHC44 740EVQLVESGGGLVQPGGSLRLSCAASGFTFS VH NYGVSWVRQAPGKGLEWVSMIWADGSTHYADTLKSRFTISRDNSKNTLYLQMNSLRAEDT AVYYCAREWQHGPVAYWGQGTLVTVSS rHC44 CDR-H1Residues 31-35 NYGVS VH of SEQ ID NO.: 740 rHC44 CDR-H2 Residues 50-65MIWADGSTHYADTLKS VH of SEQ ID NO.: 740 rHC44 CDR-H3 Residues 98-106EWQHGPVAY VH of SEQ ID NO.: 740 rHC22 741 EVQLVESGGGLVQPGGSLRLSCAASGFTFSVH NYGVTWVRQAPGKGLEWVSMIWADGSTDYA DTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC22 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 741 rHC22 CDR-H2 Residues 50-65 MIWADGSTDYADTVKG VH of SEQ IDNO.: 741 rHC22 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 741rHC81 742 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA DSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS rHC81 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 742 rHC81 CDR-H2 Residues 50-65 MIWADGSTHYADSVKS VH of SEQ IDNO.: 742 rHC81 CDR-H3 Residues 98-106 EWQHGPLAY VH of SEQ ID NO.: 742rHC18 743 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWSDGSTDYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC18 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 743 rHC18 CDR-H2 Residues 50-65 MIWSDGSTDYASSVKG VH of SEQ IDNO.: 743 rHC18 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 743rHC14 744 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPAAYWGQGTLVTVSS rHC14 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 744 rHC14 CDR-H2 Residues 50-65 MIWADGSTHYASSLKG VH of SEQ IDNO.: 744 rHC14 CDR-H3 Residues 98-106 EWQHGPAAY VH of SEQ ID NO.: 744rHC3 745 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVSWVRQAPGKGLEWVSMIWADGSTHYA SSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC3 CDR-H1 Residues 31-35 NYGVS VH of SEQID NO.: 745 rHC3 CDR-H2 Residues 50-65 MIWADGSTHYASSLKG VH of SEQ IDNO.: 745 rHC3 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 745rHC19 746 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPAAYWGQGTLVTVSS rHC19 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 746 rHC19 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 746 rHC19 CDR-H3 Residues 98-106 EWQHGPAAY VH of SEQ ID NO.: 746rHC34 747 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPSAYWGQGTLVTVSS rHC34 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 747 rHC34 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 747 rHC34 CDR-H3 Residues 98-106 EWQHGPSAY VH of SEQ ID NO.: 747rHC83 748 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS rHC83 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 748 rHC83 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 748 rHC83 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 748S4-19 749 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVEWVRQAPGKGLEWVSGIWADGSTHYA DTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-19 CDR-H1 Residues 31-35 NYGVE VH of SEQID NO.: 749 S4-19 CDR-H2 Residues 50-65 GIWADGSTHYADTVKS VH of SEQ IDNO.: 749 S4-19 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 749S4-50 750 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVEWVRQAPGKGLEWVSGIWADGSTHYA DTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS S4-50 CDR-H1 Residues 31-35 NYGVE VH of SEQID NO.: 750 S4-50 CDR-H2 Residues 50-65 GIWADGSTHYADTVKS VH of SEQ IDNO.: 750 S4-50 CDR-H3 Residues 98-106 EWQHGPVGY VH of SEQ ID NO.: 750S4-63 751 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVEWVRQAPGKGLEWVSGIWADGSTHYA DTVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS S4-63 CDR-H1 Residues 31-35 NYGVE VH of SEQID NO.: 751 S4-63 CDR-H2 Residues 50-65 GIWADGSTHYADTVKS VH of SEQ IDNO.: 751 S4-63 CDR-H3 Residues 98-106 EWQHGPVGY VH of SEQ ID NO.: 751S4-55 752 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTDYA STVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVGYWGQGTLVTVSS S4-55 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 752 S4-55 CDR-H2 Residues 50-65 MIWADGSTDYASTVKG VH of SEQ IDNO.: 752 S4-55 CDR-H3 Residues 98-106 EWQHGPVGY VH of SEQ ID NO.: 752S4-6 753 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-6 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 753 S4-6 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 753 S4-6 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 753S4-18 754 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA DSVKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS S4-18 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 754 S4-18 CDR-H2 Residues 50-65 MIWADGSTHYADSVKS VH of SEQ IDNO.: 754 S4-18 CDR-H3 Residues 98-106 EWQHGPLAY VH of SEQ ID NO.: 754S4-31 755 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVQWVRQAPGKGLEWVSGIGADGSTAYA SSLKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHSGLAYWGQGTLVTVSS S4-31 CDR-H1 Residues 31-35 NYGVQ VH of SEQID NO.: 755 S4-31 CDR-H2 Residues 50-65 GIGADGSTAYASSLKG VH of SEQ IDNO.: 755 S4-31 CDR-H3 Residues 98-106 EWQHSGLAY VH of SEQ ID NO.: 755S4-34 756 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVSWVRQAPGKGLEWVSMIWADGSTHYA DTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS S4-34 CDR-H1 Residues 31-35 NYGVS VH of SEQID NO.: 756 S4-34 CDR-H2 Residues 50-65 MIWADGSTHYADTVKG VH of SEQ IDNO.: 756 S4-34 CDR-H3 Residues 98-106 EWQHGPLAY VH of SEQ ID NO.: 756S4-74 757 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA DTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPLAYWGQGTLVTVSS S4-74 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 757 S4-74 CDR-H2 Residues 50-65 MIWADGSTHYADTVKG VH of SEQ IDNO.: 757 S4-74 CDR-H3 Residues 98-106 EWQHGPLAY VH of SEQ ID NO.: 757S4-12 758 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-12 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 758 S4-12 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 758 S4-12 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 758S4-54 759 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-54 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 759 S4-54 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 759 S4-54 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 759S4-17 760 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-17 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 760 S4-17 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 760 S4-17 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 760S4-40 761 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-40 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 761 S4-40 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 761 S4-40 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 761S4-24 762 EVQLVESGGGLVQPGGSLRLSCAASGFTFS VHNYGVTWVRQAPGKGLEWVSMIWADGSTHYA SSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREWQHGPVAYWGQGTLVTVSS S4-24 CDR-H1 Residues 31-35 NYGVT VH of SEQID NO.: 762 S4-24 CDR-H2 Residues 50-65 MIWADGSTHYASSVKG VH of SEQ IDNO.: 762 S4-24 CDR-H3 Residues 98-106 EWQHGPVAY VH of SEQ ID NO.: 762

TABLE 23 VL sequences of IgG converted clones Protein Sequence regionSEQ ID NO: 123456789012345678901234567890 hMAK195 763DIQMTQSPSSLSASVGDRVTITCKASQAVS VL.1 SAVAWYQQKPGKAPKLLIYWASTRHTGVPS VLRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYSTPFTFGQGTKLEIKR hMAK195 CDR-L1Residues 24-34 KASQAVSSAVA VL.1 of SEQ ID VL NO.: 763 hMAK195 CDR-L2Residues 50-56 WASTRHT VL.1 of SEQ ID VL NO.: 763 hMAK195 CDR-L3Residues 89-97 QQHYSTPFT VL.1 of SEQ ID VL NO.: 763 S4-24 764DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFTFGQGTKLEIKR S4-24 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 764 S4-24 CDR-L2 Residues 50-56WASTLHT VL of SEQ ID NO.: 764 S4-24 CDR-L3 Residues 89-97 QQHYRTPFT VLof SEQ ID NO.: 764 S4-40 765 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASTRHSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFSFGQGTKLEIKR S4-40 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 765 S4-40 CDR-L2 Residues 50-56 WASTRHS VL of SEQ ID NO.: 765 S4-40CDR-L3 Residues 89-97 QQHYRTPFS VL of SEQ ID NO.: 765 S4-17 766DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASTRHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFTFGQGTKLEIKR S4-17 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 766 S4-17 CDR-L2 Residues 50-56WASTRHS VL of SEQ ID NO.: 766 S4-17 CDR-L3 Residues 89-97 QQHYRTPFT VLof SEQ ID NO.: 766 S4-54 767 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASARHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYKTPFSFGQGTKLEIKR S4-54 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 767 S4-54 CDR-L2 Residues 50-56 WASARHT VL of SEQ ID NO.: 767 S4-54CDR-L3 Residues 89-97 QQHYKTPFS VL of SEQ ID NO.: 767 S4-12 768DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASARHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYKTPFTFGQGTKLEIKR S4-12 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 768 S4-12 CDR-L2 Residues 50-56WASARHT VL of SEQ ID NO.: 768 S4-12 CDR-L3 Residues 89-97 QQHYKTPFT VLof SEQ ID NO.: 768 S4-74 769 DIQMTQSPSSLSASVGDRVTITCRASQLVS VLSAVAWYQQKPGKAPKLLIYWASARHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFTFGQGTKLEIKR S4-74 CDR-L1 Residues 24-34 RASQLVSSAVA VL of SEQ IDNO.: 769 S4-74 CDR-L2 Residues 50-56 WASARHT VL of SEQ ID NO.: 769 S4-74CDR-L3 Residues 89-97 QQHYRTPFT VL of SEQ ID NO.: 769 S4-34 770DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFTFGQGTKLEIKR S4-34 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 770 S4-34 CDR-L2 Residues 50-56WASTRHT VL of SEQ ID NO.: 770 S4-34 CDR-L3 Residues 89-97 QQHYRTPFT VLof SEQ ID NO.: 770 S4-31 771 DIQMTQSPSSLSASVGDRVTITCRASQGVS VLSALAWYQQKPGKAPKLLIYWASALHSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSAPFTFGQGTKLEIKR S4-31 CDR-L1 Residues 24-34 RASQGVSSALA VL of SEQ IDNO.: 771 S4-31 CDR-L2 Residues 50-56 WASALHS VL of SEQ ID NO.: 771 S4-31CDR-L3 Residues 89-97 QQHYSAPFT VL of SEQ ID NO.: 771 S4-18 772DIQMTQSPSSLSASVGDRVTITCRASQLVS VL SAVAWYQQKPGKAPKLLIYWASTLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYSTPFTFGQGTKLEIKR S4-18 CDR-L1 Residues24-34 RASQLVSSAVA VL of SEQ ID NO.: 772 S4-18 CDR-L2 Residues 50-56WASTLHS VL of SEQ ID NO.: 772 S4-18 CDR-L3 Residues 89-97 QQHYSTPFT VLof SEQ ID NO.: 772 S4-6 773 DIQMTQSPSSLSASVGDRVTITCKASQLVS VLSAVAWYQQKPGKAPKLLIYWASTRHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSTPFTFGQGTKLEIKR S4-6 CDR-L1 Residues 24-34 KASQLVSSAVA VL of SEQ IDNO.: 773 S4-6 CDR-L2 Residues 50-56 WASTRHT VL of SEQ ID NO.: 773 S4-6CDR-L3 Residues 89-97 QQHYSTPFT VL of SEQ ID NO.: 773 S4-55 774DIQMTQSPSSLSASVGDRVTITCKASQLVS VL SAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYRTPFTFGQGTKLEIKR S4-55 CDR-L1 Residues24-34 KASQLVSSAVA VL of SEQ ID NO.: 774 S4-55 CDR-L2 Residues 50-56WASTLHT VL of SEQ ID NO.: 774 S4-55 CDR-L3 Residues 89-97 QQHYRTPFT VLof SEQ ID NO.: 774 S4-63 775 DIQMTQSPSSLSASVGDRVTITCKASQKVS VLSALAWYQQKPGKAPKLLIYWASALHSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRPPFTFGQGTKLEIKR S4-63 CDR-L1 Residues 24-34 KASQKVSSALA VL of SEQ IDNO.: 775 S4-63 CDR-L2 Residues 50-56 WASALHS VL of SEQ ID NO.: 775 S4-63CDR-L3 Residues 89-97 QQHYRPPFT VL of SEQ ID NO.: 775 S4-50 776DIQMTQSPSSLSASVGDRVTITCKASQLVS VL SAVAWYQQKPGKAPKLLIYWASALHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HYSSPYTFGQGTKLEIKR S4-50 CDR-L1 Residues24-34 KASQLVSSAVA VL of SEQ ID NO.: 776 S4-50 CDR-L2 Residues 50-56WASALHT VL of SEQ ID NO.: 776 S4-50 CDR-L3 Residues 89-97 QQHYSSPYT VLof SEQ ID NO.: 776 S4-19 777 DIQMTQSPSSLSASVGDRVTITCKASQLVS VLSAVAWYQQKPGKAPKLLIYWASTLHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPFTFGQGTKLEIKR S4-19 CDR-L1 Residues 24-34 KASQLVSSAVA VL of SEQ IDNO.: 777 S4-19 CDR-L2 Residues 50-56 WASTLHT VL of SEQ ID NO.: 777 S4-19CDR-L3 Residues 89-97 QQHYRTPFT VL of SEQ ID NO.: 777

TABLE 24 Heavy and light chain pairs of hMAK195 affinity matured clonesClone name HC LC Protein name A8 hMAK195-A8 hMAK195 VL.1 hMAK195-AM11 B5hMAK195-B5 hMAK195 VL.1 hMAK195-AM13 rHC3 hMAK195 rHC3 hMAK195 VL.1hMAK195-AM14 rHC18 hMAK195 rHC18 hMAK195 VL.1 hMAK195-AM15 rHC19 hMAK195rHC19 hMAK195 VL.1 hMAK195-AM16 rHC22 hMAK195 rHC22 hMAK195 VL.1hMAK195-AM17 rHC34 hMAK195 rHC34 hMAK195 VL.1 hMAK195-AM18 rHC60 hMAK195rHC60 hMAK195 VL.1 hMAK195-AM19 S4-6 hMAK195 S4-6 hMAK195 S4-6hMAK195-AM20 S4-12 hMAK195 S4-12 hMAK195 S4-12 hMAK195-AM21 S4-17hMAK195 S4-17 hMAK195 S4-17 hMAK195-AM22 S4-18 hMAK195 S4-18 hMAK195S4-18 hMAK195-AM23 S4-19 hMAK195 S4-19 hMAK195 S4-19 hMAK195-AM24 S4-24hMAK195 S4-24 hMAK195 S4-24 hMAK195-AM25 S4-34 hMAK195 S4-34 hMAK195S4-34 hMAK195-AM26

2.1 TNF Enzyme-Linked Immunosorbent Assay Result

TABLE 25 IgG Name EC50 in hTNFa ELISA (nM) hMAK195-AM11 0.2 hMAK195-AM130.2 hMAK195-AM14 0.051 hMAK195-AM15 0.052 hMAK195-AM16 0.056hMAK195-AM17 0.056 hMAK195-AM18 0.052 hMAK195-AM19 0.057 hMAK195-AM200.043 hMAK195-AM21 0.042 hMAK195-AM22 0.052 hMAK195-AM23 0.055hMAK195-AM24 0.053 hMAK195-AM25 0.052 hMAK195-AM26 0.061

2.2 TNF Neutralization Potency of TNF Antibodies by L929 Bioassay

TABLE 26 hu TNF neutralization IC50 rhesus TNF IgG Name (nM)neutralization IC50 (nM) hMAK195-AM11 0.259 >25 hMAK195-AM13 1.218 4.64hMAK195-AM14 0.0401 4.61 hMAK195-AM15 0.036 >150 hMAK195-AM16 0.01050.803 hMAK195-AM17 0.0031 >25 hMAK195-AM18 0.0145 0.4412 hMAK195-AM190.0126 1.206 hMAK195-AM20 0.0037 0.596 hMAK195-AM21 0.009 0.09hMAK195-AM22 0.00345 0.2705 hMAK195-AM23 0.0468 2.627 hMAK195-AM24 0.0150.557 hMAK195-AM25 0.0114 0.262 hMAK195-AM26 0.0061 0.2495

Example 3 Affinity Maturation of a Humanized Anti-Human TNF AntibodyhMAK-199

The mouse anti-human TNF antibody MAK-199 was humanized andaffinity-matured to generate a panel of humanized MAK195 variants thathave improved affinity and binding kinetics against both human and cynoTNF. Several libraries were made according to specifications below:

Three HC libraries were made after the V2I back-mutation was firstintroduced and confirmed that it did not impact scFv affinity to TNF.H1+H2 (DDK) library:

Limited mutagenesis at 7 residues (T30, N31, N35, T52a, T54, E56, T58)

Germline toggle: M34I and F63L

H1+H2 (QKQ) library:

Limited mutagenesis at 7 residues (T30, N31, N35, T52a, T54, E56, T58)

Germline toggle: M34I and F63L

Germline back-mutations: D61Q, D62K, K64Q, F67V, F69M, L71T

H3 library:

Limited mutagenesis at 12 residues 95-100, 100a-100f

Germline toggle: F91Y

LC library: library

Limited mutagenesis at 11 residues 28, 30-32, 50, 53, 91-94, 96

Germline toggles: T51A, Y71F, F87Y, and T43A/V44P (these two co-evolve)

Recombined libraries:VH libraries will be recombined with and without VL library afterlibrary diversity is reduced after at least 3 rounds of selection.

All four libraries were selected separately for the ability to bindhuman or cynomolgus monkey TNF in the presence of decreasingconcentrations of biotinylated human or cynomolgus monkey TNF antigens.All mutated CDR sequences recovered from library selections wererecombined into additional libraries and the recombined libraries weresubjected to more stringent selection conditions before individualantibodies are identified.

Table 27 provides a list of amino acid sequences of VH of the hMAK-199antibody which were subjected to the affinity maturation selectionprotocol Amino acid residues of individual CDRs of each VH sequence areindicated in bold.

TABLE 27 List of amino acid sequences of affinity matured hMAK199 VHvariants Clone SEQ ID NO: VH J644M2S1-10VH 778EVQLVQSGAEVKKPGASVKVSCKASGYTFNDYGITWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-11VH 779EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-12VH 780EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGISWVRQAPGQGLEWMGWINTYTGEPHYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-13VH 781EVQLVQSGAEVKKPGASVKVSCKASGYTFDNYGIQWVRQAPGQGLEWMGWINTYTGAPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-14VH 782EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGINWVRQAPGQGLEWMGWINTYTGKPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-15VH 783EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGMNWVRQAPGQGLEWMGWINTYTGESTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-16VH 784EVQLVQSGAEVKKPGASVKVSCKASGYTFKNYGMTWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-17VH 785EVQLVQSGAEVKKPGASVKVSCKASGYAFTDYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-18VH 786EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGEPAYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-1VH 787EVQLVQSGAEVKKPGASVKVSCKASGYTFRNYGINWVRQAPGQGLEWMGWINTYTGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-22VH 788EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGINWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-23VH 789EVQLVQSGAEVKKPGASVKVSCKASGYTFKNYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-24VH 790EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-25VH 791EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGKPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-27VH 792EVQLVQSGAEVKKPGASVKVSCKASGYTFKNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-28VH 793EVQLVQSGAEVKKPGASVKVSCKASGYTFRNYGINWVRQAPGQGLEWMGWINTYTGKPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-2VH 794EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGIXWVRQAPGQGLEWMGWINTYXGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-31VH 795EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGEPHYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-33VH 796EVQLVQSGAEVKKPGASVKVSCKASGYTFTHYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-34VH 797EVQLVQSGAEVKKPGASVKVSCKASGYTFTHYGINWVRQAPGQGLEWMGWINTYTGQPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-35VH 798EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGITWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-36VH 799EVQLVQSGAEVKKPGASVKVSCKASGYTFGNYGINWVRQAPGQGLEWMGWINTYTGKPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-37VH 800EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGRPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-38VH 801EVQLVQSGAEVKKPGASVKVSCKASGYTFKNYGINWVRQAPGQGLEWMGWINTYTGEPHYAQGFTGRVTMTTDTSTSTAYIELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-3VH 802EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGEPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-40VH 803EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGMNWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-41VH 804EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGIGWVRQAPGQGLEWMGWINTYTGKPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-43VH 805EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGVPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-44VH 806EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGIAWVRQAPGQGLEWMGWINTYTGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-45VH 807EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGVPHYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-46VH 808EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGIXWVRQAPGQGLEWMGWINTYTGEPXYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-47VH 809EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGVPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-48VH 810EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-4VH 811EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGITWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-50VH 812EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGVPQYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-51VH 813EVQLVQSGAEVKKPGASVKVSCKASGYTFQNYGINWVRQAPGQGLEWMGWINTYTGVPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-53VH 814EVQLVQSGAEVKKPGASVKVSCKASGYTFTQYGINWVRQAPGQGLEWMGWINTYTGDPHYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-54VH 815EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGLPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-55VH 816EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYNGKPMYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-56VH 817EVQLVQSGAEVKKPGASVKVSCKASGYTFRNYGITWVRQAPGQGLEWMGWINTYTGEPAYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-59VH 818EVQLVQSGAEVKKPGASVKVSCKASGYTFNHYGINWVRQAPGQGLEWMGWINTYTGRPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-5VH 819EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-60VH 820EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-64VH 821EVQLVQSGAEVKKPGASVKVSCKASGYTFDNYGINWVRQAPGQGLEWMGWINTYTGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-65VH 822EVQLVQSGAEVKKPGASVKVSCKASGYTFNDYGIIWVRQAPGQGLEWMGWINTYTGKPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-66VH 823EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-67VH 824EVQLVQSGAEVKKPGASVKVSCKASGYTFANYGMNWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-68VH 825EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGEPSYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-6VH 826EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGVPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-71VH 827EVQLVQSGAEVKKPGASVKVSCKASGYTFDHYGMNWVRQAPGQGLEWMGWINTYTGKPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-72VH 828EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGIGWVRQAPGQGLEWMGWINTYTGKPSYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-73VH 829EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-74VH 830EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGMNWVRQAPGQGLEWMGWINTYTGKPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-75VH 831EVQLVQSGAEVKKPGASVKVSCKASGYTFDNYGMNWVRQAPGQGLEWMGWINTYTGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-76VH 832EVQLVQSGAEVKKPGASVKVSCKASGYTFNSYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-77VH 833EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGITWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-79VH 834EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYNGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-7VH 835EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGIIWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-81VH 836EVQLVQSGAEVKKPGASVKVSCKASGYTFANYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-82VH 837EVQLVQSGAEVKKPGASVKVSCKASGYTFSDYGIQWVRQAPGQGLEWMGWINTYTGRPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-83VH 838EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGISWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-84VH 839EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGIQWVRQAPGQGLEWMGWINTYTGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-85VH 840EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-87VH 841EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYSGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-88VH 842EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-8VH 843EVQLVQSGAEVKKPGASVKVSCKASGYTFPNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-90VH 844EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGKTNYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-91VH 845EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGEPNYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-92VH 846EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGITWVRQAPGQGLEWMGWINTYTGEPHYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-93VH 847EVQLVQSGAEVKKPGASVKVSCKASGYTFKNYGINWVRQAPGQGLEWMGWINTYTGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-94VH 848EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGIPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-95VH 849EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-96VH 850EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYSGVPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J644M2S1-9VH 851EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2-11VH 852EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFWRTVVGTDNAMDYWGQG TTVTVSS J647M2-12VH 853EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKYSTTVVVTDYAMDYWGQG TTVTVSS J647M2-13VH 854EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDSAMDYWGQG TTVTVSS J647M2-15VH 855EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFMTTMAVTDFAMDYWGQG TTVTVSS J647M2-16VH 856EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLTTVVATDNAMDYWGQG TTVTVSS J647M2-17VH 857EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTTVIVTDNAMDYWGQG TTVTVSS J647M2-19VH 858EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFFTPVVVTDNAMDYWGQG TTVTVSS J647M2-1VH 859EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLMTTVVVTDHAMDYWGQG TTVTVSS J647M2-20VH 860EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKYLTTVVVTDSAMDYWGQG TTVTVSS J647M2-21VH 861EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFRSSVAVTDNAMDYWGQG TTVTVSS J647M2-22VH 862EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLFTTVVVTDSAMDYWGQG TTVTVSS J647M2-23VH 863EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKYLMPVVVTDYAMDYWGQG TTVTVSS J647M2-24VH 864EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKLLDAVMVTDYAMDYWGQG TTVTVSS J647M2-26VH 865EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTTVVVNDYAMDYWGQG TTVTVSS J647M2-44VH 866EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLTTVAVTDYAMDYWGQG TTVTVSS J647M2-45VH 867EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLKTVVATDDAMDYWGQG TTVTVSS J647M2-47VH 868EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLNTAVVTDYAMDYWGQG TTVTVSS J647M2-48VH 869EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARRFLTTVDVTDNAMDYWGQG TTVTVSS J647M2-4VH 870EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKYLTPVVATDFAMDYWGQG TTVTVSS J647M2-51VH 871EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKCMTTIVETDNAMDYWGQG TTVTVSS J647M2-52VH 872EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFMNTVDVTDNAMDYWGQG TTVTVSS J647M2-53VH 873EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLFTTVVVTDDAMDYWGQG TTVTVSS J647M2-54VH 874EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLMTTVVVTDYAMDYWGQG TTVTVSS J647M2-55VH 875EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLPTVVVTDYAMDYWGQG TTVTVSS J647M2-56VH 876EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKLLTTVVVTDNAMDYWGQG TTVTVSS J647M2-58VH 877EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKILTTVVVTDNAMDYWGQG TTVTVSS J647M2-70VH 878EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKVMATEVVTDYAMDYWGQG TTVTVSS J647M2-71VH 879EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLVTTVVVTDYAMDYWGQG TTVTVSS J647M2-72VH 880EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFRKPVSVTDYAMDYWGQG TTVTVSS J647M2-73VH 881EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLWTTVVVTDNAMDYWGQG TTVTVSS J647M2-74VH 882EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLTPVVVTDYAMDYWGQG TTVTVSS J647M2-75VH 883EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFRTTVVETDYCMDYWGQG TTVTVSS J647M2-76VH 884EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKYFTTVAVTDYAMDYWGQG TTVTVSS J647M2-78VH 885EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARRFLTTVEVTDLAMDYWGQG TTVTVSS J647M2-79VH 886EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLRTEVMTDYAMDYWGQG TTVTVSS J647M2-7VH 887EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLSTVAVTDSAMDYWGQG TTVTVSS J647M2-80VH 888EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKVLNTVVVTDYAMDYWGQG TTVTVSS J647M2-83VH 889EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFMNTAMVTDYAMDYWGQG TTVTVSS J647M2-84VH 890EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFSTTVVVTDYAMDYWGQG TTVTVSS J647M2-85VH 891EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKYFTTVVVTDYAMDYWGQG TTVTVSS J647M2-86VH 892EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLNTVVVTDYAMDYWGQG TTVTVSS J647M2S1-12VH 893EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFMPTVVETDYAMDYWGQG TTVTVSS J647M2S1-13VH 894EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGNPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-14VH 895EVQLVQSGAEVKKPGASVKVSCKASGYTFADYGMNWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-15VH 896EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTTVVVTDCAMDYWGQG TTVTVSS J647M2S1-17VH 897EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-18VH 898EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTTVVVTDNAMDYWGQG TTVTVSS J647M2S1-19VH 899EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLNTVVGTDYAMDYWGQG TTVTVSS J647M2S1-21VH 900EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKLLTTEAVTDYAMDYWGQG TTVTVSS J647M2S1-22VH 901EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKYSTPVVVTDYAMDYWGQG TTVTVSS J647M2S1-23VH 902EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGEPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-26VH 903EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKCLNTVAVTEHRMDYWGQG TTVTVSS J647M2S1-28VH 904EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTTVVHTDYAMDYWGQG TTVTVSS J647M2S1-30VH 905EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-31VH 906EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-32VH 907EVQLVQSGAEVKKPGASVKVSCKASGYTFANYGINWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-33VH 908EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFRTTVVLTDSAMDYWGQG TTVTVSS J647M2S1-35VH 909EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGEPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-36VH 910EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFQTPVVDTDYAMDYWGQG TTVTVSS J647M2S1-39VH 911EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFMKTRVVTDNAMDYWGQG TTVTVSS J647M2S1-40VH 912EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGIVWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-41VH 913EVQLVQSGAEVKKPGASVKVSCKASGYTFPNYGISWVRQAPGQGLEWMGWINTYTGEPSYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-43VH 914EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGEPSYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-45VH 915EVQLVQSGAEVKKPGASVKVSCKASGYTFTKYGINWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-47VH 916EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKYLTTVVATDYAMDYWGQG TTVTVSS J647M2S1-48VH 917EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLNTVVVTDYAMDYWGQG TTVTVSS J647M2S1-65VH 918EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTPVVVTDCAMDYWGQG TTVTVSS J647M2S1-66VH 919EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGEPRYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-67VH 920EVQLVQSGAEVKKPGASVKVSCKASGYTFRDYGINWVRQAPGQGLEWMGWINTYTGLPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-69VH 921EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFWTTIVVTDYAMDYWGQG TTVTVSS J647M2S1-6VH 922EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKLLTTVSATDNAMDYWGQG TTVTVSS J647M2S1-70VH 923EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLNTVVVTDYAMDYWGQG TTVTVSS J647M2S1-72VH 924EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGINWVRQAPGQGLEWMGWINTYNGEPSYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-75VH 925EVQLVQSGAEVKKPGASVKVSCKASGYTFATYGIAWVRQAPGQGLEWMGWINTYSGVPKYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-76VH 926EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFRTTAVPTDNAMDYWGQG TTVTVSS J647M2S1-77VH 927EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFLTTVVNTDSAMDYWGQG TTVTVSS J647M2S1-78VH 928EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGRG TTVTVSS J647M2S1-79VH 929EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLKTRVVTDYAMDYWGQG TTVTVSS J647M2S1-7VH 930EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-80VH 931EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLTTVVATDYAMDYWGQG TTVTVSS J647M2S1-84VH 932EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-85VH 933EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGQPTYAQGFTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-87VH 934EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFFPTMVVTDYAMDYWGQG TTVTVSS J647M2S1-88VH 935EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKFVTTMVVTDYAMDYWGQG TTVTVSS J647M2S1-8VH 936EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYAQGLTGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFLTTVVVTDYAMDYWGQG TTVTVSS J647M2S1-92VH 937EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCARKLLTTIVATDNAMDYWGQG TTVTVSS J647M2S1-93VH 938EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLMSTVVETDNAMDYWGQG TTVTVSS J647M2S1-94VH 939EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLFTVVQTDYAMDYWGQG TTVTVSS J647M2S1-96VH 940EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYYCARKLLNTVVDTDYAMDYWGQG TTVTVSS J662M2S3-14VH 941EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGIIWVRQAPGQGLEWMGWINTYTGEPHYAQKLQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTVEDVTDCAMDYWGQG TTVTVSS J662M2S3-18VH 942EVQLVQSGAEVKKPGASVKVSCKASGYTFDNYGMNWVRQAPGQGLEWMGWINTYNGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFLVEAVTDYAMDYWGQG TTVTVSS J662M2S3-28VH 943EVQLVQSGAEVKKPGASVKVSCKASGYTFRNYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTTVDVTDNAMDYWGQG TTVTVSS J662M2S3-29VH 944EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGIIWVRQAPGQGLEWMGWINTYTGVPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFNTVDVTDNAMDYWGQG TTVTVSS J662M2S3-30VH 945EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGIIWVRQAPGQGLEWMGWINTYTGEPHYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFKTMAVTDAAMDYWGQG TTVTVSS J662M2S3-34VH 946EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFRNTVAVTDYAMDYWGQG TTVTVSS J662M2S3-3VH 947EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFNTVAVTDNAMDYWGQG TTVTVSS J662M2S3-41VH 948EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFFTEDVTDYAMDYWGQG TTVTVSS J662M2S3-45VH 949EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGINWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFFTPVVVTDNAMDYWGQG TTVTVSS J662M2S3-55VH 950EVQLVQSGAEVKKPGASVKVSCKASGYTFRNYGITWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTTMDVTDNAMDYWGQG TTVTVSS J662M2S3-5VH 951EVQLVQSGAEVKKPGASVKVSCKASGYTFANYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFTTMDVTDNAMDYWGQG TTVTVSS J662M2S3-65VH 952EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKLQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFNTVDVTDNAMDYWGQG TTVTVSS J662M2S3-78VH 953EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGIIWVRQAPGQGLEWMGWINTYTGKPSYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFNTVDVTDNAMDYWGQG TTVTVSS J662M2S3-84VH 954EVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGINWVRQAPGQGLEWMGWINTYTGQPSYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFKTEAVTDYAMDYWGQG TTVTVSS J662M2S3-87VH 955EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGIIWVRQAPGQGLEWMGWINTYSGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTTMDVTDNAMDYWGQG TTVTVSS J662M2S3-96VH 956EVQLVQSGAEVKKPGASVKVSCKASGYTFNNYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKFFTTMAVTDNAMDYWGQG TTVTVSS

Table 28 provides a list of amino acid sequences of VL regions ofaffinity matured fully human TNF antibodies derived from hMAK199 Aminoacid residues of individual CDRs of each VL sequence are indicated inbold.

TABLE 28 List of amino acid sequences of affinity matured hMAK199 VLvariants Clone SEQ ID NO: VL J644M2S1-11Vk 957DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ644M2S1-73Vk 958 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ647M2-11Vk 959 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKTVKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ647M2S1-10Vk 960 DIQMTQSPSSLSASVGDRVTITCRASQDIWNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNRYPPTFGQGTKLEIKJ647M2S1-16Vk 961 DIQMTQSPSSLSASVGDRVTITCRASQDICTYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNSPPPTFGQGTKLEIKJ647M2S1-1Vk 962 DIQMTQSPSSLSASVGDRVTITCRASQAIGNYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ647M2S1-20Vk 963 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTRPPTFGQGTKLEIKJ647M2S1-24Vk 964 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSLLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTGPPTFGQGTKLEIKJ647M2S1-25Vk 965 DIQMTQSPSSLSASVGDRVTITCRASQDIYNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ647M2S1-29Vk 966 DIQMTQSPSSLSASVGDRVTITCRASQDISHYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPATFGQGTKLEIKJ647M2S1-2Vk 967 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKTVKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTPPPTFGQGTKLEIKJ647M2S1-34Vk 968 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ647M2S1-37Vk 969 DIQMTQSPSSLSASVGDRVTITCRASQEISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTMPTTFGQGTKLEIKJ647M2S1-38Vk 970 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYFASRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTPPTTFGQGTKLEIKJ647M2S1-3Vk 971 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPSTFGQGTKLEIKJ647M2S1-42Vk 972 DIQMTQSPSSLSASVGDRVTITCRASQVISNTLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNALPPTFGQGTKLEIKJ647M2S1-44Vk 973 DIQMTQSPSSLSASVGDRVTITCRASQDISTYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTPPPTFGQGTKLEIKJ647M2S1-46Vk 974 DIQMTQSPSSLSASVGDRVTITCRASQDISQYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ647M2S1-50Vk 975 DIQMTQSPSSLSASVGDRVTITCRASQDITNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTAPPTFGQGTKLEIKJ647M2S1-52Vk 976 DIQMTQSPSSLSASVGDRVTITCRASQGISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTMPPTFGQGTKLEIKJ647M2S1-56Vk 977 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ647M2S1-59Vk 978 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTRPPTFGQGTKLEIKJ647M2S1-71Vk 979 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSLLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTQPPTFGQGTKLEIKJ647M2S1-74Vk 980 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNSQPPTFGQGTKLEIKJ647M2S1-78Vk 981 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYNASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ647M2S1-7Vk 982 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSLLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNIWPPTFGQGTKLEIKJ647M2S1-9Vk 983 DIQMTQSPSSLSASVGDRVTITCRASQDISHYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-10Vk 984 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTFPPTFGQGTKLEIKJ652M2S1-13Vk 985 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ652M2S1-14Vk 986 DIQMTQSPSSLSASVGDRVTITCRASQDISNVLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ652M2S1-15Vk 987 DIQMTQSPSSLSASVGDRVTITCRASQDIYKYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTMPPTFGQGTKLEIKJ652M2S1-17Vk 988 DIQMTQSPSSLSASVGDRVTITCRASQEIFSYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNMGPPTFGQGTKLEIKJ652M2S1-18Vk 989 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTQPPTFGQGTKLEIKJ652M2S1-1Vk 990 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTWPPTFGQGTKLEIKJ652M2S1-22Vk 991 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTRPPTFGQGTKLEIKJ652M2S1-23Vk 992 DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTFPPTFGQGTKLEIKJ652M2S1-25Vk 993 DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTRPPTFGQGTKLEIKJ652M2S1-26Vk 994 DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ652M2S1-27Vk 995 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYASGLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTWPPTFGQGTKLEIKJ652M2S1-28Vk 996 DIQMTQSPSSLSASVGDRVTITCRASQDISRYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTQPPTFGQGTKLEIKJ652M2S1-29Vk 997 DIQMTQSPSSLSASVGDRVTITCRASQDIATYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTMPPTFGQGTKLEIKJ652M2S1-31Vk 998 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTFPPTFGQGTKLEIKJ652M2S1-33Vk 999 DIQMTQSPSSLSASVGDRVTITCRASQRIGNYLNWYQQKPGKTVKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-34Vk 1000 DIQMTQSPSSLSASVGDRVTITCRASQEISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNSQPPTFGQGTKLEIKJ652M2S1-35Vk 1001 DIQMTQSPSSLSASVGDRVTITCRASQDIANYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ652M2S1-37Vk 1002 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTFPPTFGQGTKLEIKJ652M2S1-38Vk 1003 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTQPPTFGQGTKLEIKJ652M2S1-3Vk 1004 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTPPPTFGQGTKLEIKJ652M2S1-40Vk 1005 DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ652M2S1-41Vk 1006 DIQMTQSPSSLSASVGDRVTITCRASQDIGNFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTRPPTFGQGTKLEIKJ652M2S1-42Vk 1007 DIQMTQSPSSLSASVGDRVTITCRASQDITNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTPPPTFGQGTKLEIKJ652M2S1-45Vk 1008 DIQMTQSPSSLSASVGDRVTITCRASQDISDYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNMWPPTFGQGTKLEIKJ652M2S1-47Vk 1009 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTMPPTFGQGTKLEIKJ652M2S1-48Vk 1010 DIQMTQSPSSLSASVGDRVTITCRASQDISHYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ652M2S1-49Vk 1011 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTMPPTFGQGTKLEIKJ652M2S1-51Vk 1012 DIQMTQSPSSLSASVGDRVTITCRASQDISQYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTRPPTFGQGTKLEIKJ652M2S1-52Vk 1013 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNMRPPTFGQGTKLEIKJ652M2S1-53Vk 1014 DIQMTQSPSSLSASVGDRVTITCRASQDISTYLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-55Vk 1015 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTGPPTFGQGTKLEIKJ652M2S1-56Vk 1016 DIQMTQSPSSLSASVGDRVTITCRASQNINNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTMPPTFGQGTKLEIKJ652M2S1-57Vk 1017 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTPPPTFGQGTKLEIKJ652M2S1-61Vk 1018 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTVPPTFGQGTKLEIKJ652M2S1-62Vk 1019 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSKLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNIFPPTFGQGTKLEIKJ652M2S1-64Vk 1020 DIQMTQSPSSLSASVGDRVTITCRASQGIYNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-67Vk 1021 DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ652M2S1-69Vk 1022 DIQMTQSPSSLSASVGDRVTITCRASQEISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTGPPTFGQGTKLEIKJ652M2S1-6Vk 1023 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTPPPTFGQGTKLEIKJ652M2S1-71Vk 1024 DIQMTQSPSSLSASVGDRVTITCRASQDISDYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTWPPTFGQGTKLEIKJ652M2S1-73Vk 1025 DIQMTQSPSSLSASVGDRVTITCRASQDIWKYLNWYQQKPGKAPKLLIYYASRLQSVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTLPPTFGQGTKLEIKJ652M2S1-75Vk 1026 DIQMTQSPSSLSASVGDRVTITCRASQDISTYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTWPPTFGQGTKLEIKJ652M2S1-77Vk 1027 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTPPPTFGQGTKLEIKJ652M2S1-78Vk 1028 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNAPPPTFGQGTKLEIKJ652M2S1-79Vk 1029 DIQMTQSPSSLSASVGDRVTITCRASQDIYKFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-80Vk 1030 DIQMTQSPSSLSASVGDRVTITCRASQDIFNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-82Vk 1031 DIQMTQSPSSLSASVGDRVTITCRASQDISNTLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTLPPTFGQGTKLEIKJ652M2S1-84Vk 1032 DIQMTQSPSSLSASVGDRVTITCRASQHISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ652M2S1-86Vk 1033 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNMPPPTFGQGTKLEIKJ652M2S1-87Vk 1034 DIQMTQSPSSLSASVGDRVTITCRASQDITNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTVPPTFGQGTKLEIKJ652M2S1-8Vk 1035 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYFTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGNTQPPTFGQGTKLEIKJ652M2S1-90Vk 1036 DIQMTQSPSSLSASVGDRVTITCRASQDISKFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYYCQQGNTRPPTFGQGTKLEIKJ652M2S1-91Vk 1037 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTFPPTFGQGTKLEIKJ652M2S1-92Vk 1038 DIQMTQSPSSLSASVGDRVTITCRASQDIYNVLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGITLPPTFGQGTKLEIKJ652M2S1-93Vk 1039 DIQMTQSPSSLSASVGDRVTITCRASQHISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTWPPTFGQGTKLEIKJ652M2S1-95Vk 1040 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTQPSTFGQGTKLEIKJ652M2S1-9Vk 1041 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ662M2S3-13Vk 1042 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNSWPPTFGQGTKLEIKJ662M2S3-15Vk 1043 DIQMTQSPSSLSASVGDRVTITCRASQDIYNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ662M2S3-21Vk 1044 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTWPPTFGQGTKLEIKJ662M2S3-22Vk 1045 DIQMTQSPSSLSASVGDRVTITCRASQDISQYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTWPPTFGQGTKLEIKJ662M2S3-34Vk 1046 DIQMTQSPSSLSASVGDRVTITCRASQDIYDVLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQGITLPPTFGQGTKLEIKJ662M2S3-3Vk 1047 DIQMTQSPSSLSASVGDRVTITCRASQDIENYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ662M2S3-41Vk 1048 DIQMTQSPSSLSASVGDRVTITCRASQNIENFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTWPPTFGQGTKLEIKJ662M2S3-56Vk 1049 DIQMTQSPSSLSASVGDRVTITCRASQDIYNYLNWYQQKPGKAPKLLIYYTSRLQGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTPPPTFGQGTKLEIKJ662M2S3-64Vk 1050 DIQMTQSPSSLSASVGDRVTITCRASQDIASYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ662M2S3-78Vk 1051 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKVPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSL QPEDFATYFCQQGNTQPPTFGQGTKLEIKJ662M2S3-84Vk 1052 DIQMTQSPSSLSASVGDRVTITCRASQNIYNVLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYFCQQGNTMPPTFGQGTKLEIK

TABLE 29 Amino acid residues observed in affinity matured hMAK-199antibodies MAK199 Heavy chain variable region (SEQ ID NO: 1077)MAK199VH.2a1234567890123456789012345678901234567890123456789012a345678901EIQLVQSGAEVKKPGASVKVSCKASGYTFT NYGMN WVRQAPGQGLEWMG WINTYTGEPTYAD V                           ND  II                   N K S  Q                             AH   T                   S V H                             ST   Q                     Q N                             RS   S                     R M                             DQ   G                     L K                             KK   A                     S A                             P    V                     N R                             Q                          I Q                             M                          D D                             G                          A                             E234567890123456789012abc345678901234567890abcdefg1234567890123 DFKGRFTFTLDTSTSTAYMELSSLRSEDTAVYFCAR KFLTTVVVTDYAMDY WGQGTTVTVSS GLT  V MT                      Y   RLFNPMDASENT KQ                                 NYMKVEAEM SR                                     IRSSAEMN CC                                     VSRARSD  H                                     CWL IMG  D                                      QP QII  I                                      VF GPQ  F                                      ND D P  V                                      GM   N  L                                      CA   L  A                                           H Mak199 Light chain variableregion (SEQ ID NO: 1078) Mak199Vk.1a1234567890123456789012345678901234567890123456789012345678901DIQMTQSPSSLSASVGDRVTITC RASQDISNYLN WYQQKPGKTVKLLIY YTSRLQS GVPSR                           N YQV          AP     FA L                           E ESF          V      N  K                           H AKT                    G                           G TT                            V WH                           R GD                            A NR                             F                              C234567890123456789012345678901234567890123456aFSGSGSGTDYTLTISSLQPEDFATYFC QQGNTLPPT FGQGTKLEIK         F               Y    ISW T                                MQ S                               IP A                                AM                               RR                                 F                                G                                 V                                Y                                 A

TABLE 30 Individual hMAK-199 VH sequences from converted clones ProteinSequence region SEQ ID NO: 123456789012345678901234567890 J662M2S3 1053EVQLVQSGAEVKKPGASVKVSCKASGYTFA #10 VH NYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYYCARKLFTTMDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 10 VH of SEQ ID NO.: 1053J662M2S3# CDR-H2 Residues 50-66 WINTYTGKPTYAQKFQG 10 VH of SEQ ID NO.:1053 J662M2S3# CDR-H3 Residues 99-112 RASQDISQYLN 10 VH of SEQ ID NO.:1053 J662M2S3# 1054 EVQLVQSGAEVKKPGASVKVSCKASGYTFN 13 VHNYGIIWVRQAPGQGLEWMGWINTYTGKPTY AQKLQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFNTVDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 13 VH of SEQ ID NO.: 1054 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKLQG 13 VH of SEQ ID NO.: 1054 J662M2S3# CDR-H3 Residues99-112 KLFNTVDVTDNAMD 13 VH of SEQ ID NO.: 1054 J662M2S3# 1055EVQLVQSGAEVKKPGASVKVSCKASGYTFN 15 VH NYGIIWVRQAPGQGLEWMGWINTYTGVPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYYCARKLFNTVDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 15 VH of SEQ ID NO.: 1055J662M2S3# CDR-H2 Residues 50-66 WINTYTGVPTYAQKFQG 15 VH of SEQ ID NO.:1055 J662M2S3# CDR-H3 Residues 99-112 KLFNTVDVTDNAMD 15 VH of SEQ IDNO.: 1055 J662M2S3# 1056 EVQLVQSGAEVKKPGASVKVSCKASGYTFN 16 VHNYGIIWVRQAPGQGLEWMGWINTYTGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFNTVAVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 16 VH of SEQ ID NO.: 1056 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKFQG 16 VH of SEQ ID NO.: 1056 J662M2S3# CDR-H3 Residues99-112 KLFNTVAVTDNAMD 16 VH of SEQ ID NO.: 1056 J662M2S3# 1057EVQLVQSGAEVKKPGASVKVSCKASGYTFR 21 VH NYGIIWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYFCARKLFTTVDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGII 21 VH of SEQ ID NO.: 1057J662M2S3# CDR-H2 Residues 50-66 WINTYTGKPTYAQKFQG 21 VH of SEQ ID NO.:1057 J662M2S3# CDR-H3 Residues 99-112 KLFTTVDVTDNAMD 21 VH of SEQ IDNO.: 1057 J662M2S3# 1058 EVQLVQSGAEVKKPGASVKVSCKASGYTFN 34 VHNYGINWVRQAPGQGLEWMGWINTYTGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKFRNTVAVTDYAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGIN 34 VH of SEQ ID NO.: 1058 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKFQG 34 VH of SEQ ID NO.: 1058 J662M2S3# CDR-H3 Residues99-112 KFRNTVAVTDYAMD 34 VH of SEQ ID NO.: 1058 J662M2S3# 1059EVQLVQSGAEVKKPGASVKVSCKASGYTFR 36 VH NYGITWVRQAPGQGLEWMGWINTYTGKPTYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYFCARKLFTTMDVTDNAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGIT 36 VH of SEQ ID NO.: 1059J662M2S3# CDR-H2 Residues 50-66 WINTYTGKPTYAQKFQG 36 VH of SEQ ID NO.:1059 J662M2S3# CDR-H3 Residues 99-112 KLFTTMDVTDNAMD 36 VH of SEQ IDNO.: 1059 J662M2S3# 1060 EVQLVQSGAEVKKPGASVKVSCKASGYTFA 45 VHNYGIIWVRQAPGQGLEWMGWINTYTGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYYCARKLFTTMDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 45 VH of SEQ ID NO.: 1060 J662M2S3# CDR-H2 Residues 50-66WINTYTGKPTYAQKFQG 45 VH of SEQ ID NO.: 1060 J662M2S3# CDR-H3 Residues99-112 KLFTTMDVTDNAMD 45 VH of SEQ ID NO.: 1060 J662M2S3# 1061EVQLVQSGAEVKKPGASVKVSCKASGYTFS 58 VH NYGINWVRQAPGQGLEWMGWINTYTGQPSYAQKFQGRVTMTTDTSTSTAYMELSSLRSED TAVYYCARKLFKTEAVTDYAMDYWGQGTTV TVSSJ662M2S3# CDR-H1 Residues 31-35 NYGIN 58 VH of SEQ ID NO.: 1061J662M2S3# CDR-H2 Residues 50-66 WINTYTGQPSYAQKFQG 58 VH of SEQ ID NO.:1061 J662M2S3# CDR-H3 Residues 99-112 KLFKTEAVTDYAMD 58 VH of SEQ IDNO.: 1061 J662M2S3# 1062 EVQLVQSGAEVKKPGASVKVSCKASGYTFN 72 VHNYGIIWVRQAPGQGLEWMGWINTYSGKPTY AQKFQGRVTMTTDTSTSTAYMELSSLRSEDTAVYFCARKLFTTMDVTDNAMDYWGQGTTV TVSS J662M2S3# CDR-H1 Residues 31-35NYGII 72 VH of SEQ ID NO.: 1062 J662M2S3# CDR-H2 Residues 50-66WINTYSGKPTYAQKFQG 72 VH of SEQ ID NO.: 1062 J662M2S3# CDR-H3 Residues99-112 KLFTTMDVTDNAMD 72 VH of SEQ ID NO.: 1062

TABLE 31 Individual hMAK-199 clones VL sequences Protein Sequence regionSEQ ID NO: 123456789012345678901234567890 J662M2S3# 1063DIQMTQSPSSLSASVGDRVTITCRASQDIS 10 VL QYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQ GNTWPPTFGQGTKLEIK J662M2S3#10 CDR-L1Residues 24-34 RASQDISQYLN VL of SEQ ID NO.: 1063 J662M2S3#10 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1063 J662M2S3#10 CDR-L3Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 1063 J662M2S3#13 1064DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQ GNSWPPTFGQGTKLEIK J662M2S3#13 CDR-L1Residues 24-34 RASQDISNYLN VL of SEQ ID NO.: 1064 J662M2S3#13 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1064 J662M2S3#13 CDR-L3Residues 89-97 QQGNSWPPT VL of SEQ ID NO.: 1064 J662M2S3#15 1065DIQMTQSPSSLSASVGDRVTITCRASQDIY VL NYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQ GNTQPPTFGQGTKLEIK J662M2S3#15 CDR-L1Residues 24-34 RASQDIYNYLN VL of SEQ ID NO.: 1065 J662M2S3#15 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1065 J662M2S3#15 CDR-L3Residues 89-97 QQGNTQPPT VL of SEQ ID NO.: 1065 J662M2S3#16 1066DIQMTQSPSSLSASVGDRVTITCRASQDIE VL NYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQ GNTQPPTFGQGTKLEIK J662M2S3#16 CDR-L1Residues 24-34 RASQDIENYLN VL of SEQ ID NO.: 1066 J662M2S3#16 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1066 J662M2S3#16 CDR-L3Residues 89-97 QQGNTQPPT VL of SEQ ID NO.: 1066 J662M2S3#21 1067DIQMTQSPSSLSASVGDRVTITCRASQDIS VL NYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQ GNTWPPTFGQGTKLEIK J662M2S3#21 CDR-L1Residues 24-34 RASQDISNYLN VL of SEQ ID NO.: 1067 J662M2S3#21 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1067 J662M2S3#21 CDR-L3Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 1067 J662M2S3#34 1068DIQMTQSPSSLSASVGDRVTITCRASQDIY VL DVLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ GITLPPTFGQGTKLEIK J662M2S3#34 CDR-L1Residues 24-34 RASQDIYDVLN VL of SEQ ID NO.: 1068 J662M2S3#34 CDR-L2Residues 50-56 YASRLQS 4 VL of SEQ ID NO.: 1068 J662M2S3#34 CDR-L3Residues 89-97 QQGITLPPT VL of SEQ ID NO.: 1068 J662M2S3#36 1069DIQMTQSPSSLSASVGDRVTITSRASQDIS VL NYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQ GNTWPPTFGQGTKLEIK J662M2S3#36 CDR-L1Residues 24-34 RASQDISNYLN VL of SEQ ID NO.: 1069 J662M2S3#36 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1069 J662M2S3#36 CDR-L3Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 1069 J662M2S3#45 1070DIQMTQSPSSLSASVGDRVTITSRASQDIS VL QYLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQ GNTWPPTFGQGTKLEIK J662M2S3#45 CDR-L1Residues 24-34 RASQDISQYLN VL of SEQ ID NO.: 1070 J662M2S3#45 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1070 J662M2S3#45 CDR-L3Residues 89-97 QQGNTWPPT VL of SEQ ID NO.: 1070 J662M2S3#58 1071DIQMTQSPSSLSASVGDRVTITSRASQNIY VL NVLNWYQQKPGKAPKLLIYYASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQ GNTMPPTFGQGTKLEIK J662M2S3#58 CDR-L1Residues 24-34 RASQNIYNVLN VL of SEQ ID NO.: 1071 J662M2S3#58 CDR-L2Residues 50-56 YASRLQS VL of SEQ ID NO.: 1071 J662M2S3#58 CDR-L3Residues 89-97 QQGNTMPPT VL of SEQ ID NO.: 1071 J662M2S3#72 1072DIQMTQSPSSLSASVGDRVTITSRASQDIS VL NFLNWYQQKPGKAPKLLIYYTSRLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQ GNTQPPTFGQGTKLEIK J662M2S3#72 CDR-L1Residues 24-34 RASQDISNFLN VL of SEQ ID NO.: 1072 J662M2S3#72 CDR-L2Residues 50-56 YTSRLQS VL of SEQ ID NO.: 1072 J662M2S3#72 CDR-L3Residues 89-97 QQGNTQPPT VL of SEQ ID NO.: 1072

TABLE 32 hMAK199 affinity matured scFv clones converted to full lengthIgG ScFv Full length IgG clone name HC plasmid LC plasmid (protein) nameJ662M2S3#10 pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662 hMAK199-AM1J662M2S3#10 M2S3#10 J662M2S3#13 pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662hMAK199-AM2 J662M2S3#13 M2S3#13 J662M2S3#15 pHybE-hCg1,z,non-a V2pHybE-hCk V3 J662 hMAK199-AM3 J662M2S3#15 M2S3#15 J662M2S3#16pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662 hMAK199-AM4 J662M2S3#16 M2S3#16J662M2S3#21 pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662 hMAK199-AM5J662M2S3#21 M2S3#21 J662M2S3#34 pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662hMAK199-AM6 J662M2S3#34 M2S3#34 J662M2S3#36 pHybE-hCg1,z,non-a V2pHybE-hCk V3 J662 hMAK199-AM7 J662M2S3#36 M2S3#36 J662M2S3#45pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662 hMAK199-AM8 J662M2S3#45 M2S3#45J662M2S3#58 pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662 hMAK199-AM9J662M2S3#58 M2S3#58 J662M2S3#72 pHybE-hCg1,z,non-a V2 pHybE-hCk V3 J662hMAK199-AM10 J662M2S3#72 M2S3#72

3.1 TNF Enzyme-Linked Immunosorbent Assay Result

TABLE 33 hMAK199 affinity matured full length IgG IgG Name EC50 in hTNFaELISA (nM) hMAK199-AM1 0.016 hMAK199-AM2 0.016 hMAK199-AM3 0.019hMAK199-AM4 0.050 hMAK199-AM5 0.078 hMAK199-AM6 0.035 hMAK199-AM7 0.100hMAK199-AM8 0.219 hMAK199-AM9 0.032 hMAK199-AM10 0.014

3.2 TNF Neutralization Potency of TNF Antibodies by L929 Bioassay

TABLE 34 hu TNF rhesus TNF neutralization IgG Name neutralization IC50(nM) IC50 (nM) hMAK199-AM1 0.054 0.012 hMAK199-AM2 0.029 0.010hMAK199-AM3 0.051 0.019 hMAK199-AM4 0.028 0.005 hMAK199-AM5 0.087 0.020hMAK199-AM6 0.033 0.004 hMAK199-AM7 0.095 0.051 hMAK199-AM8 0.247 0.204hMAK199-AM9 0.163 0.089 hMAK199-AM10 0.048 0.034

Example 4 Example 4.4 Affinity Determination Using BIACORE Technology

TABLE 35 Reagent for Biacore Analyses Antigen Vendor Designation VendorCatalog # TNFα Recombinant Human TNF- R&D 210-TA α/TNFSF1A systems

BIACORE Methods:

The BIACORE assay (Biacore, Inc. Piscataway, N.J.) determines theaffinity of binding proteins with kinetic measurements of on-rate andoff-rate constants. Binding of binding proteins to a target antigen (forexample, a purified recombinant target antigen) is determined by surfaceplasmon resonance-based measurements with a Biacore® 1000 or 3000instrument (Biacore®AB, Uppsala, Sweden) using running HBS-EP (10 mMHEPES [pH 7.4], 150 mM NaCl, 3 mM EDTA, and 0.005% surfactant P20) at25° C. All chemicals are obtained from Biacore® AB (Uppsala, Sweden) orotherwise from a different source as described in the text. For example,approximately 5000 RU of goat anti-mouse IgG, (Fey), fragment specificpolyclonal antibody (Pierce Biotechnology Inc, Rockford, Ill., US)diluted in 10 mM sodium acetate (pH 4.5) is directly immobilized acrossa CM5 research grade biosensor chip using a standard amine coupling kitaccording to manufacturer's instructions and procedures at 25 μg/ml.Unreacted moieties on the biosensor surface are blocked withethanolamine. Modified carboxymethyl dextran surface in flowcell 2 and 4is used as a reaction surface. Unmodified carboxymethyl dextran withoutgoat anti-mouse IgG in flow cell 1 and 3 is used as the referencesurface. For kinetic analysis, rate equations derived from the 1:1Langmuir binding model are fitted simultaneously to association anddissociation phases of all eight injections (using global fit analysis)with the use of Biaevaluation 4.0.1 software. Purified antibodies arediluted in HEPES-buffered saline for capture across goat anti-mouse IgGspecific reaction surfaces. Antibodies to be captured as a ligand (25μg/ml) are injected over reaction matrices at a flow rate of 5μl/minute. The association and dissociation rate constants, k_(on) (M¹s¹) and k_(off) (s⁻¹), are determined under a continuous flow rate of 25μl/minute. Rate constants are derived by making kinetic bindingmeasurements at different antigen concentrations ranging from 10-200 nM.The equilibrium dissociation constant (M) of the reaction betweenantibodies and the target antigen is then calculated from the kineticrate constants by the following formula: K_(D)=k_(off)/k_(on). Bindingis recorded as a function of time and kinetic rate constants arecalculated. In this assay, on-rates as fast as 10⁶M⁻¹ s⁻¹ and off-ratesas slow as 10⁻⁶ s⁻¹ can be measured.

The binding proteins herein are expected to have beneficial propertiesin this regard, including high affinity, slow off rate, and highneutralizing capacity.

Example 4.5 Neutralization of Human TNF-α

L929 cells are grown to a semi-confluent density and harvested using0.25% trypsin

(Gibco#25300). The cells are washed with PBS, counted and resuspended at1E6 cells/mL in assay media containing 4 μg/mL actinomycin D. The cellsare seeded in a 96-well plate (Costar#3599) at a volume of 100 μL and5E4 cells/well. The binding proteins and control IgG are diluted to a 4×concentration in assay media and serial 1:4 dilutions are performed. ThehuTNF-α is diluted to 400 pg/mL in assay media. Binding protein sample(200 μL) is added to the huTNF-α (200 μL) in a 1:2 dilution scheme andallowed to incubate for 0.5 hour at room temperature.

The binding protein/human TNF-α solution is added to the plated cells at100 μL for a final concentration of 100 pg/mL huTNF-α and 150 nM-0.0001nM binding protein. The plates are incubated for 20 hours at 37° C., 5%CO₂. To quantitate viability, 100 μL is removed from the wells and 10 μLof WST-1 reagent (Roche cat#11644807001) is added. Plates are incubatedunder assay conditions for 3.5 hours. The plates are read at OD 420-600nm on a Spectromax 190 ELISA plate reader.

The binding proteins herein are expected to have beneficial propertiesin this regard, including high affinity, slow off rate, and highneutralizing capacity.

Example 4.6 Treatment

A patient requiring treatment with a TNF-α binding protein may have adisease with immune and inflammatory elements, such as autoimmunediseases, particularly those associated with inflammation, includingCrohn's disease, psoriasis (including plaque psoriasis), arthritis(including rheumatoid arthritis, psoratic arthritis, osteoarthritis, orjuvenile idiopathic arthritis), multiple sclerosis, and ankylosingspondylitis. Therefore, the binding proteins herein may be used to treatthese disorders.

Administration of the TNF-α binding protein may occur by subcutaneousinjection. If the patient has rheumatoid arthritis, psoratic arthritis,or ankylosing spondyitis, the patient may receive 40 mg every other weekas a starting dose and 40 mg every week, if necessary to achievetreatment goals. If the patient has juvenile idiopathic arthritis andweighs from 15 kg to <30 kg, the patient may receive 20 mg every otherweek, and if >30 kg, 40 mg every other week. If the patient has Crohn'sdisease, the patient may receive an initial dose of 160 mg (four 40 mginjections in one day or two 40 mg injections per day for twoconsecutive days) followed by 80 mg two weeks later, and another twoweeks later begin a maintenance dose of 40 mg every other week. If thepatient has plaque psoriasis, the patient may receive an 80 mg initialdose, followed by 40 mg every other week starting one week after initialdose.

The binding protein may be provided in a single-use prefilled pen (40mg/0.8 mL), a single-use prefilled glass syringe (40 mg/0.8 mL or 20mg/0.4 mL).

INCORPORATION BY REFERENCE

The contents of all cited references (including literature references,patents, patent applications, and websites) that are cited throughoutthis application are hereby expressly incorporated by reference in theirentirety, as are the references cited therein. The practice disclosedherein will employ, unless otherwise indicated, conventional techniquesof immunology, molecular biology and cell biology, which are well knownin the art.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting of the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are therefore intended to be embracedherein.

1-18. (canceled)
 19. A method for treating a mammal comprisingadministering to the mammal an effective amount of a pharmaceuticalcomposition comprising a binding protein that binds human TNFα, thebinding protein comprising at least one heavy chain variable region (VHregion) and at least one light chain variable region (VL region),wherein the VH region comprises the amino acid sequences of the threecomplementarity determining regions (CDRs) from SEQ ID NO: 1077 or theamino acid sequence of SEQ ID NO: 1077, wherein the VL region comprisesthe amino acid sequence of the three CDRs from SEQ ID NO: 1078 or theamino acid sequence of SEQ ID NO:
 1078. 20. (canceled)
 21. A method forreducing human TNF-α activity in a human subject suffering from adisorder in which TNF-α activity is detrimental, the method comprisingadministering to the human subject a binding protein of claim 19 suchthat human TNF-α activity in the human subject is reduced and/ortreatment is achieved.
 22. A method for treating a patient sufferingfrom a disorder in which TNF-α is detrimental comprising administeringto the patient the binding protein of claim 19 either before,concurrent, or after the administration to the patient of a secondagent, wherein the second agent is selected from the group consisting ofan antibody, or fragment thereof, capable of binding human IL-12; PGE2;LPA; NGF; CGRP; SubP; RAGE; histamine; a histamine receptor blocker;bradykinin; IL-1alpha; IL-1beta; VEGF; PLGF; methotrexate; acorticosteroid, a glucocorticoid receptor modulator; cyclosporin,rapamycin, FK506, and a non-steroidal anti-inflammatory agent.
 23. Themethod of claim 21, wherein the disorder is an autoimmune and/orinflammatory disorder.
 24. The method of claim 23, wherein the disorderis selected from the group consisting of Crohn's disease, psoriasis,plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis,osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis,and ankylo sing spondylitis.
 25. The method of claim 23, wherein thedisorder is selected from the group consisting of a respiratorydisorder; asthma; allergic and nonallergic asthma; asthma due toinfection; asthma due to infection with respiratory syncytial virus(RSV); chronic obstructive pulmonary disease (COPD); a conditioninvolving airway inflammation; eosinophilia; fibrosis and excess mucusproduction; cystic fibrosis; pulmonary fibrosis; an atopic disorder;atopic dermatitis; urticaria; eczema; allergic rhinitis; allergicenterogastritis; an inflammatory and/or autoimmune condition of theskin; an inflammatory and/or autoimmune condition of gastrointestinalorgans; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn'sdisease; an inflammatory and/or autoimmune condition of the liver; livercirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or Cvirus; scleroderma; tumors or cancers; hepatocellular carcinoma;glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; abacterial infection; a parasitic infection; HTLV-1 infection;suppression of expression of protective type 1 immune responses, andsuppression of expression of a protective type 1 immune response duringvaccination. 26-29. (canceled)
 30. The method of claim 22, wherein thedisorder is an autoimmune and/or inflammatory disorder.
 31. The methodof claim 30, wherein the disorder is selected from the group consistingof Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoidarthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathicarthritis, multiple sclerosis, and ankylo sing spondylitis.
 32. Themethod of claim 30, wherein the disorder is selected from the groupconsisting of a respiratory disorder; asthma; allergic and nonallergicasthma; asthma due to infection; asthma due to infection withrespiratory syncytial virus (RSV); chronic obstructive pulmonary disease(COPD); a condition involving airway inflammation; eosinophilia;fibrosis and excess mucus production; cystic fibrosis; pulmonaryfibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema;allergic rhinitis; allergic enterogastritis; an inflammatory and/orautoimmune condition of the skin; an inflammatory and/or autoimmunecondition of gastrointestinal organs; inflammatory bowel diseases (IBD);ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmunecondition of the liver; liver cirrhosis; liver fibrosis; liver fibrosiscaused by hepatitis B and/or C virus; scleroderma; tumors or cancers;hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; aviral infection; a bacterial infection; a parasitic infection; HTLV-1infection; suppression of expression of protective type 1 immuneresponses, and suppression of expression of a protective type 1 immuneresponse during vaccination.
 33. A method for treating a mammalcomprising administering to the mammal an effective amount of apharmaceutical composition comprising a binding protein that binds humanTNFα, the binding protein comprising at least one heavy chain variableregion (VH region), wherein the VH region comprises the amino acidsequences of the three complementarity determining regions (CDRs) fromSEQ ID NO: 1077 or the amino acid sequence of SEQ ID NO:
 1077. 34. Amethod for reducing human TNF-α activity in a human subject sufferingfrom a disorder in which TNF-α activity is detrimental, the methodcomprising administering to the human subject the binding protein ofclaim 33 such that human TNF-α activity in the human subject is reducedand/or treatment is achieved.
 35. A method for treating a patientsuffering from a disorder in which TNF-α is detrimental comprisingadministering to the patient the binding protein of claim 33 eitherbefore, concurrent, or after the administration to the patient of asecond agent, wherein the second agent is selected from the groupconsisting of an antibody, or fragment thereof, capable of binding humanIL-12; PGE2; LPA; NGF; CGRP; SubP; RAGE; histamine; a histamine receptorblocker; bradykinin; IL-1alpha; IL-1beta; VEGF; PLGF; methotrexate; acorticosteroid, a glucocorticoid receptor modulator; cyclosporin,rapamycin, FK506, and a non-steroidal anti-inflammatory agent.
 36. Themethod of claim 34, wherein the disorder is an autoimmune and/orinflammatory disorder.
 37. The method of claim 36, wherein the disorderis selected from the group consisting of Crohn's disease, psoriasis,plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis,osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis,and ankylo sing spondylitis.
 38. The method of claim 36, wherein thedisorder is selected from the group consisting of a respiratorydisorder; asthma; allergic and nonallergic asthma; asthma due toinfection; asthma due to infection with respiratory syncytial virus(RSV); chronic obstructive pulmonary disease (COPD); a conditioninvolving airway inflammation; eosinophilia; fibrosis and excess mucusproduction; cystic fibrosis; pulmonary fibrosis; an atopic disorder;atopic dermatitis; urticaria; eczema; allergic rhinitis; allergicenterogastritis; an inflammatory and/or autoimmune condition of theskin; an inflammatory and/or autoimmune condition of gastrointestinalorgans; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn'sdisease; an inflammatory and/or autoimmune condition of the liver; livercirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or Cvirus; scleroderma; tumors or cancers; hepatocellular carcinoma;glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; abacterial infection; a parasitic infection; HTLV-1 infection;suppression of expression of protective type 1 immune responses, andsuppression of expression of a protective type 1 immune response duringvaccination.
 39. The method of claim 35, wherein the disorder is anautoimmune and/or inflammatory disorder.
 40. The method of claim 39,wherein the disorder is selected from the group consisting of Crohn'sdisease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis,psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis,multiple sclerosis, and ankylo sing spondylitis.
 41. The method of claim39, wherein the disorder is selected from the group consisting of arespiratory disorder; asthma; allergic and nonallergic asthma; asthmadue to infection; asthma due to infection with respiratory syncytialvirus (RSV); chronic obstructive pulmonary disease (COPD); a conditioninvolving airway inflammation; eosinophilia; fibrosis and excess mucusproduction; cystic fibrosis; pulmonary fibrosis; an atopic disorder;atopic dermatitis; urticaria; eczema; allergic rhinitis; allergicenterogastritis; an inflammatory and/or autoimmune condition of theskin; an inflammatory and/or autoimmune condition of gastrointestinalorgans; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn'sdisease; an inflammatory and/or autoimmune condition of the liver; livercirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or Cvirus; scleroderma; tumors or cancers; hepatocellular carcinoma;glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; abacterial infection; a parasitic infection; HTLV-1 infection;suppression of expression of protective type 1 immune responses, andsuppression of expression of a protective type 1 immune response duringvaccination.
 42. A method for treating a mammal comprising administeringto the mammal an effective amount of a pharmaceutical compositioncomprising a binding protein that binds human TNFα, the binding proteincomprising at least one light chain variable region (VL region), whereinthe VL region comprises the amino acid sequences of the threecomplementarity determining regions (CDRs) from SEQ ID NO: 1078 or theamino acid sequence of SEQ ID NO:
 1078. 43. A method for reducing humanTNF-α activity in a human subject suffering from a disorder in whichTNF-α activity is detrimental, the method comprising administering tothe human subject the binding protein of claim 40 such that human TNF-αactivity in the human subject is reduced and/or treatment is achieved.44. A method for treating a patient suffering from a disorder in whichTNF-α is detrimental comprising administering to the patient the bindingprotein of claim 40 either before, concurrent, or after theadministration to the patient of a second agent, wherein the secondagent is selected from the group consisting of an antibody, or fragmentthereof, capable of binding human IL-12; PGE2; LPA; NGF; CGRP; SubP;RAGE; histamine; a histamine receptor blocker; bradykinin; IL-1alpha;IL-1beta; VEGF; PLGF; methotrexate; a corticosteroid, a glucocorticoidreceptor modulator; cyclosporin, rapamycin, FK506, and a non-steroidalanti-inflammatory agent.
 45. The method of claim 43, wherein thedisorder is an autoimmune and/or inflammatory disorder.
 46. The methodof claim 45, wherein the disorder is selected from the group consistingof Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoidarthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathicarthritis, multiple sclerosis, and ankylo sing spondylitis.
 47. Themethod of claim 45, wherein the disorder is selected from the groupconsisting of a respiratory disorder; asthma; allergic and nonallergicasthma; asthma due to infection; asthma due to infection withrespiratory syncytial virus (RSV); chronic obstructive pulmonary disease(COPD); a condition involving airway inflammation; eosinophilia;fibrosis and excess mucus production; cystic fibrosis; pulmonaryfibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema;allergic rhinitis; allergic enterogastritis; an inflammatory and/orautoimmune condition of the skin; an inflammatory and/or autoimmunecondition of gastrointestinal organs; inflammatory bowel diseases (IBD);ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmunecondition of the liver; liver cirrhosis; liver fibrosis; liver fibrosiscaused by hepatitis B and/or C virus; scleroderma; tumors or cancers;hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; aviral infection; a bacterial infection; a parasitic infection; HTLV-1infection; suppression of expression of protective type 1 immuneresponses, and suppression of expression of a protective type 1 immuneresponse during vaccination.
 48. The method of claim 44, wherein thedisorder is an autoimmune and/or inflammatory disorder.
 49. The methodof claim 48, wherein the disorder is selected from the group consistingof Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoidarthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathicarthritis, multiple sclerosis, and ankylo sing spondylitis.
 50. Themethod of claim 48, wherein the disorder is selected from the groupconsisting of a respiratory disorder; asthma; allergic and nonallergicasthma; asthma due to infection; asthma due to infection withrespiratory syncytial virus (RSV); chronic obstructive pulmonary disease(COPD); a condition involving airway inflammation; eosinophilia;fibrosis and excess mucus production; cystic fibrosis; pulmonaryfibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema;allergic rhinitis; allergic enterogastritis; an inflammatory and/orautoimmune condition of the skin; an inflammatory and/or autoimmunecondition of gastrointestinal organs; inflammatory bowel diseases (IBD);ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmunecondition of the liver; liver cirrhosis; liver fibrosis; liver fibrosiscaused by hepatitis B and/or C virus; scleroderma; tumors or cancers;hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; aviral infection; a bacterial infection; a parasitic infection; HTLV-1infection; suppression of expression of protective type 1 immuneresponses, and suppression of expression of a protective type 1 immuneresponse during vaccination.
 51. The method of claim 19, wherein thebinding protein: (a) modulates a biological function of the TNF-α; (b)neutralizes the TNF-α; (c) diminishes the ability of the TNF-α to bindto its receptor; (d) diminishes the ability of pro-human TNF-α,mature-human TNF-α, or truncated-human TNF-α to bind to its receptor;and/or (e) reduces one or more of TNF-dependent cytokine production,TNF-dependent cell killing, TNF-dependent inflammation, TNF-dependentbone erosion, and TNF-dependent cartilage damage.
 52. The method ofclaim 19, wherein the binding protein comprises: (a) a heavy chainconstant region comprising an amino acid sequence of SEQ ID NO:2 or SEQID NO: 3; and (b) a light chain constant region comprising an amino acidsequence of SEQ ID NO:4 or SEQ ID NO:
 5. 53. The method of claim 19, theat least one heavy chain variable region (VH region) comprising: (a)three CDRs from any one of SEQ ID NOs: 74-83 and 778-956; or (b) any oneof SEQ ID NOs: 74-83 and 778-956.
 54. The method of claim 19, the atleast one light chain variable region (VL region) comprising: (a) threeCDRs from any one of SEQ ID NOs: 84-93 and 957-1052; or (b) any one ofSEQ ID NOs: 84-93 and 957-1052.
 55. The method of claim 19, the at leastone heavy chain variable region (VH region) comprising: (a) three CDRsfrom any one of SEQ ID NOs: 74-83, 778-956; or (b) the sequence of anyone of SEQ ID NOs: 74-83 and 778-956; and the at least one light chainvariable region (VL region) comprising: (c) three CDRs from any one ofSEQ ID NOs: 84-93 and 957-1052; or (d) the sequence of any one of SEQ IDNOs: 84-93 and 957-1052.
 56. The method of claim 55, wherein the VHregion comprises the sequence of SEQ ID NO: 74 and the VL regioncomprises the sequence of SEQ ID NO: 84.